Shp2 phosphatase inhibitors and methods of use thereof

ABSTRACT

The present disclosure relates to novel compounds including formula (X) and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with SHP2 deregulation with the compounds and compositions of the disclosure.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S.provisional application Ser. No. 62/646,099, filed Mar. 21, 2018;62/649,834, filed Mar. 29, 2018; 62/646,083, filed Mar. 21, 2018;62/661,902, filed Apr. 24, 2018; and 62/737,819, filed Sep. 27, 2018;the contents of each of which are hereby incorporated by referenceherein in their entirety.

BACKGROUND

Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2(SHP2) is a protein tyrosine phosphatase encoded by the PTPN11 gene.SHP2 contains two Src homology 2 (SH2) NH2-terminal domains and aC-terminal protein-tyrosine phosphatase domain. It is ubiquitouslyexpressed in various tissues and cell types. SHP2 plays an importantrole in diverse signaling pathways to regulate cellular biologicalprocesses and is involved in the signaling pathways of a variety ofgrowth factors and cytokines. Within a single signaling pathway, SHP2can play both positive (signal enhancing) and negative (signaldiminishing) roles in intracellular signaling processes. SHP2 isbelieved to function by dephosphorylating its associated signalingmolecules, thereby attenuating the local signaling flow. However, themain effect of SHP2 action in most signaling pathways (e.g., growthfactor, cytokine, and extracellular matrix receptors) is to enhancesignal transduction. For example, SHP2 is a positive regulator of theERK/MAPK signaling pathway, playing a key role in regulating cellularproliferation and survival. (For a review of SHP2 phosphatase, see, e.g,K. S. Grossman et al., Adv. Cancer Res. 2010, 106, 53-89; and referencescited therein.)

In the basal state, SHP2 is normally auto-inhibited due tointramolecular interactions between its N-terminal SH2 (N—SH2) domainand its catalytic (PTP) domain, which blocks access to the catalyticsite. Activating proteins that interact with the SH2 domains induce aconformational change that reverses this inhibition and allows substrateaccess to the catalytic site. Mutations in the PTPN11 gene that affectthe N—SH2 or PTP domain residues involved in basal inhibition of SHP2result in more readily activatable forms of SHP2 protein, which can leadto unregulated or increased SHP2 activity. Such activated mutants ofSHP2 have been associated with developmental disorders such as Noonansyndrome, where nearly all mutated forms of SHP2 demonstrate increasedPTP activity. Thus, there is a need for SHP2 phosphatase inhibitorcompounds and methods for treating cancer and other disorders with thesecompounds.

SUMMARY

In some embodiments, the present disclosure provides a compound ofFormula Ia or Ib, or a pharmaceutically acceptable salt or stereoisomerthereof, represented by:

wherein

D is selected from the group consisting of: phenyl, a 5- or 6-memberedheteroaryl having one or two heteroatoms each independently selectedfrom the group consisting of S, O or N, and C₃₋₆cycloalkyl, wherein D isoptionally substituted on an available carbon with one or twosubstituents each independently selected from R^(D1), and, optionallysubstituted, on nitrogen, if present, with one or two substituents eachindependently selected from R^(D2);

U is C, CR⁴ or N;

V is C, CR⁴ or N; wherein at least one of U or V must be C, CR⁴ or N;

B is fused to D such that the two atoms shared by D and B are bothcarbon or one carbon and one nitrogen;

R⁴ is independently selected from the group consisting of hydrogen,—C(O)N(R⁶)₂, —N(R⁶)₂, and —C₁₋₃alkyl-N(R⁶)₂;

R⁶ is independently for each occurrence selected from the groupconsisting of H, —(C₁-C₆)alkyl, —C(O)OC₁₋₄alkyl, and phenyl;

R^(D) is selected from the group consisting of hydroxyl, cyano, halogen,and —N(R⁶)₂;

R² is selected from —(C₁-C₆)alkyl and phenyl;

X is selected from the group consisting of a bond, —O—, —NR^(X1)—, and—S(O)_(w)— (wherein w is 0, 1 or 2);

R¹ is a ring moiety selected from the group consisting of a 8-12membered bicyclic heteroaryl, phenyl, a 5-7 membered monocyclicheteroaryl, and a 4-7 membered heterocyclyl, wherein the ring moiety mayoptionally be substituted with one, two or more substituents eachindependently selected from the group consisting of R¹⁰, —OR¹⁰,—S(O),R¹⁰ (wherein w is 0, 1 or 2), —C₁₋₆alkyl-S(O)_(w)—C₁₋₃alkyl,—N(R¹⁰)₂, —N(CO)R¹⁰, —N—S(O)—R¹⁰ (where w is 0, 1 or 2), —OS(O)_(w)—R¹⁰(wherein w is 0, 1, or 2), —S(O)—N(R¹⁰)₂ (wherein w is 0, 1 or 2),—S(O)(NH)R¹⁰, —N(H)—SO₂—C₁₋₃alkyl, —N(SO₂—C₁₋₃alkyl)₂, P(O)(R¹⁰)₂,—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, oxo, halogen, hydroxyl, cyano, nitro,—C(═N—OR^(a))—C₁₋₃alkyl, —C(═N—OR^(a))—H, —S(O)(NR^(a))—C₁₋₃alkyl,phenyl (optionally substituted with one, two or three halogen,—O-phenyl, C₁₋₃alkyl or C₁₋₃haloalkyl), C₁₋₃alkyl, C₂₋₆alkynyl,C₁₋₃haloalkyl, C₃₋₆ cycloalkyl, heterocyclyl (optionally substitutedwith one, two or three halogen, oxo, C₁₋₃alkyl or C₁₋₃haloalkyl), andheteroaryl (optionally substituted with one, two or three halogen,—C(O)N(R¹⁰)₂, C₁₋₃alkyl, C₁₋₃alkyl-O—C₁₋₃alkyl, C₁₋₃alkyl-OH, orC₁₋₃haloalkyl);

R¹⁰ is independently selected from the group consisting of hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl,C₂₋₆heteroalkyl, heterocycloalkyl, aryl, and heteroaryl; whereinC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₅₋₆ cycloalkenyl,C₂₋₆heteroalkyl, heterocycloalkyl, aryl, and heteroaryl may optionallybe substituted by one, two, three or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,—NR^(a)C(O)—R²⁰, —C(O)—R²⁰, —C(NR^(a))—R^(b), —NR^(a)R^(b), C₁₋₆alkyl,C₁₋₆haloalkyl and C₁₋₆alkoxy;

R²⁰ is selected from the group consisting of hydrogen, hydroxyl,halogen, —NR^(a)R^(b), C₁₋₆alkyl and C₁₋₆alkoxy;

R^(X1) is selected from the group consisting of hydrogen, —(C₁-C₆)alkyland phenyl; and

R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen and C₁₋₃alkyl.

The present disclosure also provides, for example, pharmaceuticalcompositions containing the compounds described herein. Further, thedisclosure provides a method of inhibiting SHP2 phosphatase activity ina subject by administering a therapeutically effective amount of acompound or composition described herein, to a subject, e.g., a human,in need.

The present disclosure further provides, for example, a method oftreating a disorder in a subject by administering a therapeuticallyeffective amount of a compound or composition described herein, to asubject in need thereof. Examples of disorders include Noonan syndrome,neutropenia, diabetes, neuroblastoma, melanoma, acute myeloid leukemia,juvenile leukemia, juvenile myelomonocytic leukemia, breast cancer, lungcancer, and colorectal cancer. In addition to the compound orcomposition described herein, such method may include administration ofa therapeutically effective amount of an antibody, an antibody-drugconjugate, an immunomodulator, or a histone deacetylase inhibitor.

The present disclosure is based, in part, on certain discoveries whichare described more fully in the Examples section of the presentapplication. For example, the present disclosure is based, in part, onthe discovery of compounds disclosed herein, and the SHP2 phosphataseinhibition exhibited by such compounds.

These and other embodiments of the disclosure are further described inthe following sections of the application, including the DetailedDescription, Examples, and Claims. Still other objects and advantages ofthe disclosure will become apparent by those of skill in the art fromthe disclosure herein, which are simply illustrative and notrestrictive. Thus, other embodiments will be recognized by theordinarily skilled artisan without departing from the spirit and scopeof the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts an isobologram illustrating synergistic growthinhibition of KYSE520 (squamous-cell carcinoma of the head and neckcells) using erlotinib (EGFR inhibitor) and a SHP2 inhibitor of theinstant disclosure.

FIG. 1B. depicts an isobologram illustrating synergistic growthinhibition of NCI-H3122 (non-small cell lung cancer cells) usingcrizotinib (ALK inhibitor) and a SHP2 inhibitor of the instantdisclosure.

FIG. 2A. Depicts an isobologram illustrating synergistic growthinhibition of NCI-N87 (gastric cancer cells) using selumetinib (MEKinhibitor) and a SHP2 inhibitor of the instant disclosure.

FIG. 2B. Depicts an isobologram illustrating synergistic growthinhibition of NCI-H23 (KRAS G12C mutant non-small cell lung cancercells) using ARS-1620 (KRAS G12C inhibitor) and a SHP2 inhibitor of theinstant disclosure.

FIG. 3. an isobologram illustrating synergistic growth inhibition ofHuH-7 (hepatocellular carcinoma cells) using AZD-4547 (FGFR inhibitor)and a SHP2 inhibitor of the instant disclosure.

DETAILED DESCRIPTION

Activating SHP2 mutations have been detected in juvenile myelomonocyticleukemia (e.g., Q506P), chronic myelomonocytic leukemia (e.g., Y63C),neuroblastoma (e.g., T507K), melanoma (e.g., R138Q), acute myeloidleukemia (e.g., G503V), breast cancer, lung cancer (e.g., E76V),colorectal cancer (e.g., E76G). (M. Bentires-Alj et al., in Cancer Res.2004, 64, 8816-8820; and references cited therein.

SHP2 phosphatase inhibitors are disclosed, e.g., in WO 2015/107493; WO2015/107494; WO 2015/107495; and J. G. Fortanet et al., in J. Med. Chem.2016, DOI: 10.1021/acs.jmedchem.6b00680; and references cited therein.The effects of SHP2 phsophatase inhibition are described, e.g., Y.-N. P.Chen et al., in Nature, 2016, doi:10.1038/nature18621; J. Wang et al.,in J. Clin. Invest. 2016, 126, 2077-2092; and references cited therein.

The compounds and/or compositions of the disclosure, alone or incombination with other treatments, may be effective in treating,reducing, and/or suppressing disorders related to SHP2 phosphataseactivity such as, e.g., Noonan syndrome, Leopard Syndrome, diabetes,neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocyticleukemia (JMML), chronic myelomonocytic leukemia, acute myeloidleukemia, HER2-positive breast cancer, triple-negative breast cancer,ductal carcinoma of the breast, invasive ductal carcinoma of the breast,non-small cell lung cancer (including adenocarcinoma of the lung),colorectal cancer, esophageal cancer, gastric cancer, squamous-cellcarcinoma of the head and neck (SCCHN), neutropenia (Kostmann'ssyndrome), and systemic lupus erythematosus. See, e.g, N. Aceto et al.Nature Medicine, 2012, 28,529-538; C. M. Furcht et al. Oncogene, 2013,32, 2346-2355; V. E. Schneeberger et al. Oncotarget, 2015, 6, 6191-6202;P. Cai et al., Biomedicine & Pharmacotherapy 2014, 68, 285-290; andreferences cited therein.

The methods described herein may also include additionally administeringa therapeutically effective amount of an antibody, an antibody-drugconjugate, an immunomodulator, or a histone deacetylase inhibitor.

Abbreviations and Definitions

As described herein, compounds of the disclosure may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this disclosure arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R¹⁰;—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R¹⁰;—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R¹⁰; —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄C(O)SR^(∘);—(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R¹⁰; —OC(O)(CH₂)₀₋₄SR^(∘);—SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R¹⁰; —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂;—C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘);—C(O)C(O)R¹⁰; —C(O)CH₂C(O)R¹⁰; —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R¹⁰; —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂;—P(O)(OR^(∘))R^(∘); —P(O)R¹⁰ ₂; —OP(O)R¹⁰ ₂; —OP(O)(OR^(∘))₂; —SiR^(∘)₃; —(C₁₋₄ straight or branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straightor branched alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may besubstituted as defined below and is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃₀—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein each R isindependently hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R,taken together with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “isomer” as used herein refers to a compound having theidentical chemical formula but different structural or opticalconfigurations. The term “stereoisomer” as used herein refers to andincludes isomeric molecules that have the same molecular formula butdiffer in positioning of atoms and/or functional groups in the space.All stereoisomers of the present compounds (e.g., those which may existdue to asymmetric carbons on various substituents), includingenantiomeric forms and diastereomeric forms, are contemplated within thescope of this disclosure.

The term “tautomer” as used herein refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another. It is understood thattautomers encompass valence tautomers and proton tautomers (also knownas prototropic tautomers). Valence tautomers include interconversions byreorganization of some of the bonding electrons. Proton tautomersinclude interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations.

The term “isotopic substitution” as used herein refers to thesubstitution of an atom with its isotope. The term “isotope” as usedherein refers to an atom having the same atomic number as that of atomsdominant in nature but having a mass number (neutron number) differentfrom the mass number of the atoms dominant in nature. It is understoodthat a compound with an isotopic substitution refers to a compound inwhich at least one atom contained therein is substituted with itsisotope. Atoms that can be substituted with its isotope include, but arenot limited to, hydrogen, carbon, and oxygen. Examples of the isotope ofa hydrogen atom include ²H (also represented as D) and ³H. Examples ofthe isotope of a carbon atom include ¹³C and ¹⁴C. Examples of theisotope of an oxygen atom include ¹⁸O.

The term “alkyl”, as used herein, unless otherwise indicated, refers toa monovalent aliphatic hydrocarbon radical having a straight chain,branched chain, monocyclic moiety, or polycyclic moiety or combinationsthereof, wherein the radical is optionally substituted at one or morecarbons of the straight chain, branched chain, monocyclic moiety, orpolycyclic moiety or combinations thereof with one or more substituentsat each carbon, wherein the one or more substituents are independentlyC₁-C₁₀ alkyl. Examples of “alkyl” groups include methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, and the like.

The terms “heteroaryl” or “heteroaromatic group” as used herein refersto a monocyclic aromatic 5-6 membered ring system containing one or moreheteroatoms, for example one to three heteroatoms, such as nitrogen,oxygen, and sulfur, or a 8-10 membered bicyclic unsaturated or partiallyunsaturated ring system containing one or more heteroatoms, for exampleone to three heteroatoms, such as nitrogen, oxygen, and sulfur. Wherepossible, said heteroaryl ring may be linked to the adjacent radicalthough carbon or nitrogen. Examples of heteroaryl rings include but arenot limited to furan, thiophene, pyrrole, thiazole, oxazole,isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine orpyrimidine, tetrahydroquinoline, etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated 4-10 membered monocyclic and bicyclic ringstructures, including bridged or fused rings, and whose ring structuresinclude one to three heteroatoms, such as nitrogen, oxygen, and sulfur.Where possible, heterocyclyl rings may be linked to the adjacent radicalthrough carbon or nitrogen.

The term “pharmaceutically acceptable salt” is intended to include saltsderived from inorganic or organic acids including, e.g., hydrochloric,hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic,lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic,citric, methanesulfonic, benzenesulfonic, benzoic, malonic,trifluroacetic, trichloroacetic, naphthalene-2 sulfonic and other acids;and salts derived from inorganic or organic bases including, e.g.,sodium, potassium, calcium, magnesium, zinc, ammonia, lysine, arginine,histidine, polyhydroxylated amines or tetrafluoroborate. Exemplarypharmaceutically acceptable salts are found, e.g., in Berge, et al. (J.Pharm. Sci. 1977, 66(1), 1; and Gould, P. L., Int. J Pharmaceutics 1986,33, 201-217; (each hereby incorporated by reference in its entirety).Pharmaceutically acceptable salts are also intended to encompasshemi-salts, wherein the ratio of compound:acid is respectively 2:1.Exemplary hemi-salts are those salts derived from acids comprising twocarboxylic acid groups, such as malic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acidand citric acid. Other exemplary hemi-salts are those salts derived fromdiprotic mineral acids such as sulfuric acid. Exemplary preferredhemi-salts include, but are not limited to, hemimaleate, hemifumarate,and hemisuccinate.

As used herein the term “about” is used herein to mean approximately,roughly, around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20 percent up or down(higher or lower).

An “effective amount”, “sufficient amount” or “therapeutically effectiveamount” as used herein is an amount of a compound that is sufficient toeffect beneficial or desired results, including clinical results. Assuch, the effective amount may be sufficient, e.g., to reduce orameliorate the severity and/or duration of afflictions related to SHP2phosphatase, or one or more symptoms thereof, prevent the advancement ofconditions or symptoms related to afflictions related to SHP2phosphatase, or enhance or otherwise improve the prophylactic ortherapeutic effect(s) of another therapy. An effective amount alsoincludes the amount of the compound that avoids or substantiallyattenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results may include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminution of extent of disease or affliction, a stabilized(i.e., not worsening) state of disease or affliction, preventing spreadof disease or affliction, delay or slowing of disease or afflictionprogression, amelioration or palliation of the disease or afflictionstate and remission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment.

The phrase “in need thereof” refers to the need for symptomatic orasymptomatic relief from conditions related to SHP2 phosphatase activityor that may otherwise be relieved by the compounds and/or compositionsof the disclosure.

In some embodiments, the present disclosure provides a compound ofFormula Ia or Ib, or a pharmaceutically acceptable salt or stereoisomerthereof, represented by:

wherein

D (also described in Formulas X and XI herein as Cy^(C)) is selectedfrom the group consisting of: phenyl, a 5- or 6-membered heteroarylhaving one or two heteroatoms each independently selected from the groupconsisting of S, O or N, and C₃₋₆cycloalkyl, wherein D is optionallysubstituted on an available carbon with one or two substituents eachindependently selected from R^(D1), and, optionally substituted, onnitrogen, if present, with one or two substituents each independentlyselected from R^(D2);

U is C, CR⁴ or N;

V is C, CR⁴ or N;

-   -   wherein at least one of U or V must be C or CR⁴;

B is fused to D such that the two atoms shared by D and B are bothcarbon or one carbon and one nitrogen;

R⁴ is independently selected from the group consisting of hydrogen,—C(O)N(R⁶)₂, —N(R⁶)₂, and —C₁₋₃alkyl-N(R⁶)₂;

R⁶ is independently for each occurrence selected from the groupconsisting of H, —(C₁-C₆)alkyl, —C(O)OC₁₋₄alkyl, and phenyl;

R^(D) is selected from the group consisting of hydroxyl, cyano, halogen,and —N(R⁶)₂;

R² is selected from —(C₁-C₆)alkyl and phenyl;

X (also described in Formulas X and XI herein as L²) is selected fromthe group consisting of a bond, —O—, —NR^(X1)—, and —S(O)_(w)— (whereinw is 0, 1 or 2);

R¹ (also described in Formulas X and XI herein as R²) is a ring moietyselected from the group consisting of a 8-12 membered bicyclicheteroaryl, phenyl, a 5-7 membered monocyclic heteroaryl, and a 4-7membered heterocyclyl, wherein the ring moiety may optionally besubstituted with one, two or more substituents each independentlyselected from the group consisting of R¹⁰, —OR¹⁰, —S(O),R¹⁰ (wherein wis 0, 1 or 2), —C₁₋₆alkyl-S(O)_(w)—C₁₋₃alkyl, —N(R¹⁰)₂, —N(CO)R¹⁰,—N—S(O)_(w)—R¹⁰ (where w is 0, 1 or 2), —OS(O)_(w)—R¹⁰ (wherein w is 0,1, or 2), —S(O)—N(R¹⁰)₂ (wherein w is 0, 1 or 2), —S(O)(NH)R¹⁰,—N(H)—SO₂—C₁₋₃alkyl, —N(SO₂—C₁₋₃alkyl)₂, P(O)(R¹⁰)₂—C(O)R¹⁰, —C(O)OR¹⁰,—C(O)N(R¹⁰)₂, oxo, halogen, hydroxyl, cyano, nitro,—C(═N—OR^(a))—C₁₋₃alkyl, —C(═N—OR^(a))—H,—S(O)(NR^(a))—C₁₋₃alkyl, phenyl(optionally substituted with one, two or three halogen, —O-phenyl,C₁₋₃alkyl or C₁₋₃ haloalkyl), C₁₋₃alkyl, C₂₋₆alkynyl, C₁₋₃haloalkyl,C₃₋₆cycloalkyl, heterocyclyl (optionally substituted with one, two orthree halogen, oxo, C₁₋₃alkyl or C₁₋₃haloalkyl), and heteroaryl(optionally substituted with one, two or three halogen, —C(O)N(R¹⁰)₂,C₁₋₃alkyl, C₁₋₃alkyl-O—C₁₋₃alkyl, C₁₋₃alkyl-OH, or C₁₋₃haloalkyl);

R¹⁰ is independently selected from the group consisting of hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl,C₂₋₆heteroalkyl, heterocycloalkyl, aryl, and heteroaryl; whereinC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₅₋₆ cycloalkenyl,C₂₋₆heteroalkyl, heterocycloalkyl, aryl, and heteroaryl may optionallybe substituted by one, two, three or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,—NR^(a)C(O)—R²⁰, —C(O)—R²⁰, —C(NR^(a))—R^(b), —NR^(a)R^(b), C₁₋₆alkyl,C₁₋₆haloalkyl and C₁₋₆alkoxy;

R²⁰ is selected from the group consisting of hydrogen, hydroxyl,halogen, —NR^(a)R^(b), C₁₋₆alkyl and C₁₋₆alkoxy;

R^(X1) is selected from the group consisting of hydrogen, —(C₁-C₆)alkyland phenyl; and

R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen and C₁₋₃alkyl.

In some embodiments, D is selected from the group consisting of:

-   -   wherein * and + represent fusion points of attachment to ring B.

In some embodiments, X is a bond, R¹ is a nitrogen containing ringmoiety and R¹ is bound through the nitrogen.

In some embodiments, R¹ is selected from the group consisting of1,2,3,4-tetrahydroquinolin-1-yl,1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl,1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinoxalin-1-yl,1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-1-yl, 1H-benzo[d]imidazol-1-yl,indolin-1-yl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl,2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl, isoindolin-2-yl,2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-4-yl,2-(3,4-dihydroisoquinolin-1(2H)-one),2-(3,4-dihydroisoquinolin-1(2H)-one),2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl, piperidin-1-yl,1-(1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one),1,2,3,4-tetrahydro-1,8-naphthyridin-1-yl,1-(3,4-dihydro-1,5-naphthyridin-2(1H)-one),2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl,1-(2,3-dihydroquinolin-4(1H)-one),2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl,1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl,5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-4-yl,3,4-dihydroquinoxalin-1-yl-2(1H)-one,2,3,4,6-tetrahydro-1,6-naphthyridin-1-yl-5(1H)-one,1,2,3,4-tetrahydroisoquinolin-2-yl,1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl,1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl,3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl 1 1-dioxide,1,2,3,4-tetrahydropyrazino[2,3-d]pyridazin-1-yl,1,4-dihydropyrido[3,4-b]pyrazin-1-yl-3(2H)-one,5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl,5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl,1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-1-yl,5,8-dihydropteridin-5-yl-7(6H)-one,4,5,6,7-tetrahydrothieno[3,2-b]pyridin-4-yl, or5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-5-yl wherein the nitrogenring moiety may be optionally substituted with one or two substituentseach independently selected from the group consisting of Cl, F, —CN,C₁₋₄alkyl, —OC₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl,C₅₋₆cycloalkenyl, —C(H)═N—OCH₃, —C(H)═N—OH, —C(CH₃)═N—OH,—(CH₂)₀₋₁C(O)NH₂, —(CH₂)₀₋₁C(O)NHC₁₋₄alkyl, —(CH₂)O₁C(O)N(C₁₋₄alkyl)₂,—(CH₂)₀₋₁C(O)OC₁₋₄alkyl, —(CH₂)₀₋₁C(O)OH, —S(O)₂C₁₋₄alkyl, —(CH₂)₀₋₁NH₂,—(CH₂)₀₋₁NHC₁₋₄ alkyl, —(CH₂)O₁(C₁₋₄alkyl)₂, —(CH₂)₀₋₁NH(CO)C₁₋₄alkyl,phenyl, optionally substituted heteroaryl and optionally substitutedheterocyclyl, wherein C₁₋₄alkyl or C₃₋₆cycloalkyl may be optionallysubstituted with one, two or three fluorine atoms, one or two hydroxylgroups, or one or two —OC₁₋₂alkyl groups.

In some embodiments, heteroaryl is selected from the group consisting of2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,4-triazol-3-yl, thiazol-2-yl,pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, oxazol-2-yl,oxazol-5-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-5-yl,1,3,4-thiadiazol-2-yl, and 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl,1,2,4-triazol-2-yl, 1,3,4-triazol-2-yl; wherein heteroaryl may beoptionally substituted with C₁₋₂alkyl (optionally substituted with one,two or three fluorine atoms, one or two 2 hydroxyl groups, or one or two—OC₁₋₂alkyl groups).

In some embodiments, heterocyclyl is selected from the group consistingof tetrahydrofuran-3-yl, pyrrolidine-1-yl, piperazin-1-yl,piperidin-4-yl, piperidin-1-yl, 1,2,3,6-tetrahydropyridin-4-yl,2,5-dihydrofuran-3-yl, piperazin-1-yl-3-one, morpholino,tetrahydropyran-2-yl, or 1,2,4-oxadiazo-3-yl-5-one, wherein heterocyclylmay be optionally substituted with hydroxyl or C₁₋₂alkyl (optionallysubstituted with one, two or three fluorine atoms, one or two 2 hydroxylgroups, or one or two —OC₁₋₂alkyl groups).

In some embodiments, R¹ is a 1,2,3,4-tetrahydroquinoline moietyoptionally substituted with one, two or three halo, C₁₋₃alkyl orC₁₋₃haloalkyl), C₁₋₃alkyl, C₁₋₃haloalkyl, and heteroaryl (optionallysubstituted with one, two or three halogens, C₁₋₃alkyl,C₁₋₃alkyl-O—C₁₋₃alkyl, C₁₋₃alkyl-OH, or C₁₋₃haloalkyl).

In some embodiments, R¹ is a 1,2,3,4-tetrahydro-1,5-naphthyridine moietyoptionally substituted with one, two or three halo, C₁₋₃alkyl,C₁₋₃haloalkyl, and heteroaryl (optionally substituted with one, two orthree halogens, —C(O)N(R¹⁰)₂, C₁₋₃alkyl, C₁₋₃alkyl-O—C₁₋₃alkyl,C₁₋₃alkyl-OH, or C₁₋₃haloalkyl).

In some embodiments, R¹ is phenyl; wherein phenyl may optionally besubstituted by one, two, or three substituents each independentlyselected from the group consisting of —OR¹⁰, halogen, and cyano.

In some embodiments, R¹ is pyridyl; wherein pyridyl may optionally besubstituted by one, two, or three substituents each independentlyselected from the group consisting of —OR¹⁰, halogen, and cyano.

In some embodiments, R¹ is indolyl or indolinyl, wherein indolyl orindolinyl may optionally be substituted with one, two, or threesubstituents each independently selected from the group consisting of—OR¹⁰, halogen, and cyano; and wherein indolyl or indolinyl is boundthrough carbon.

Also disclosed herein, for example, is a compound of Formula II, or apharmaceutically acceptable salt or stereoisomer thereof, whereinFormula II is represented by:

wherein:

D is selected from the group consisting of: phenyl, a 5- or 6-memberedheteroaryl having one or two heteroatoms independently selected from thegroup consisting of S, O or N, and C₃₋₆cycloalkyl, wherein D isoptionally substituted on a carbon with one or two substituents eachindependently selected from R^(D1), and, optionally substituted, onnitrogen, if present, with one or two substituents each independentlyselected from R^(D2);

B is fused to D such that the two atoms shared by D and B are bothcarbon;

Z² is selected from the group consisting of CR²² and N;

Z¹ is selected from the group consisting of: NR⁶¹, C(R²³)₂; C(O), and O;

R² is selected from the group consisting of hydrogen, halogen, cyano,hydroxyl, N(R⁶)₂, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkyoxy,—C(O)N(R⁶)₂, heterocycloalkyl, phenyl, and heteroaryl, whereinC₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkyoxy, heterocycloalkyl, phenyl, andheteroaryl may each be substituted by one, two or three or moresubstituents each selected from the group consisting of halo,—C(O)—OR²⁶, —C(O)R²⁶, —C(O)N(R⁶)₂, —N(R⁶)₂, C₁₋₃ alkyl (optionallysubstituted by hydroxyl or methoxy), C₁-C₃alkyoxy, and C₁₋₃haloalkyl;

R²⁹ is selected from the group consisting of hydrogen, halogen, cyano,N(R⁶)₂, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkyoxy, —C(O)N(R⁶)₂,heterocycloalkyl, phenyl, and heteroaryl, wherein C₁-C₆alkyl,C₃-C₆cycloalkyl, C₁-C₆alkyoxy, heterocycloalkyl, phenyl, and heteroarylmay each be substituted by one, two or three or more substituents eachselected from the group consisting of halo, —C(O)R²⁶, C(O)—OR 26,—C(O)N(R⁶)₂, N(R⁶)₂, C₁₋₃ alkyl (optionally substituted with hydroxyl ormethoxy) and C₁₋₃haloalkyl;

R²², for each occurrence, is independently selected from the groupconsisting of hydrogen, halogen, cyano, hydroxyl, N(R⁶)₂, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₁-C₆alkyoxy, —C(O)N(R⁶)₂, heterocycloalkyl, phenyl,and heteroaryl, wherein C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkyoxy,heterocycloalkyl, phenyl, and heteroaryl may each be substituted by one,two or three or more substituents each selected from the groupconsisting of halo, —C(O)—OR²⁶, C(O)R²⁶, —C(O)N(R⁶)₂, N(R⁶)₂, C₁₋₃alkyl(optionally substituted with hydroxyl or methoxy), C₁-C₂alkyoxy, andC₁₋₂haloalkyl;

R²³ independently, for each occurrence, is selected from the groupconsisting of H, halogen, and C₁-C₆alkyl;

R²⁴ is selected from the group consisting of H, halogen, and C₁-C₆alkyl;

R²⁶ is selected from the group consisting of hydrogen and C₁₋₃alkyl;

-   -   R⁴ is independently selected from the group consisting of        hydrogen, —C(O)N(R⁶)₂, and —N(R⁶)₂;    -   R⁶ is selected, independently for each occurrence, from the        group consisting of hydrogen, —(C₁-C₆)alkyl and phenyl;    -   R⁶¹ is selected from the group consisting of hydrogen,        —(C₁-C₆)alkyl, —C(O)—(C₁-C₆)alkyl, C₃₋₆ cycloalkyl (optionally        substituted with one or two hydroxyl, C₁₋₂alkyl, and C₁₋₂        alkoxy), and phenyl;    -   R^(D1) is selected from the group consisting of hydroxyl, cyano,        halogen, and, —N(R⁶)₂; and    -   R^(D2) is selected from —(C₁-C₆)alkyl and phenyl.

In some embodiments, D is selected from the group consisting of:

-   -   wherein * and + represent fusion points of attachment to ring B.

In some embodiments, Z² is N. In some embodiments, Z² is CH. In someembodiments, Z¹ is C(R²³)₂.

In some embodiments, R²³ for each occurrence is hydrogen. In someembodiments, R²³ for each occurrence is methyl.

In some embodiments, R²² and R²⁴, for each occurrence, is hydrogen.

In some embodiments, R²¹ is selected from the group consisting ofhydrogen, halogen, CF₃, N(R⁶)₂, C(O)N(R⁶)₂, heteroaryl, and phenyl. Insome embodiments, R²¹ is C(O)NHCH₃.

In some embodiments, R²¹ is heteroaryl. In some embodiments, R²¹ isselected from the group consisting of selected from the group consistingof:

In some embodiments, R²¹ is hydrogen.

Also disclosed herein, for example, is a compound of Formula III, or apharmaceutically acceptable salt or stereoisomer thereof, representedby:

wherein:

A (also described herein for Formulas X and XI as R² where L² ofFormulas X and XI is a covalent bond) is selected from the groupconsisting of:

wherein:

R¹⁷ is selected from the group consisting of H, Cl, F, CHF₂, CF₃, —CN,C₁₋₄alkyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, —OC₁₋₄alkyl, —O-heteroaryl,C₂₋₄alkenyl, C₂₋₄alkynyl, —C═N—OC₁₋₄alkyl, —C═N—OH, —C(C₁₋₄alkyl)=N—OH,—(CH₂)₀₋₁C(O)NH₂, —(CH₂)₀₋₁C(O)NHC₁₋₄alkyl,—(CH₂)₀₋₁C(O)NHC₁₋₄alkyl-heteroaryl, —(CH₂)₀₋₁C(O)N(C₁₋₄alkyl)₂,—(CH₂)₀₋₁C(O)OC₁₋₄alkyl, —(CH₂)₀₋₁C(O)OH, —(CH₂)₀₋₁S(O)₂C₁₋₄alkyl,—(CH₂)₀₋₁NH₂, —(CH₂)₀₋₁NHC₁₋₄alkyl, —(CH₂)O₁(C₁₋₄ alkyl)₂,—(CH₂)₀₋₁NH(CO)C₁₋₄alkyl, phenyl, heteroaryl, and heterocyclyl,

-   -   wherein heteroaryl and O-heteroaryl may optionally be        substituted with one or more C₁₋₂alkyl (optionally substituted        with one, two or three fluorine atoms, one or two hydroxyl        groups, or one or two —OC₁₋₂alkyl groups); and    -   wherein heterocyclyl may optionally be substituted with one or        more hydroxyl or C₁₋₂alkyl (optionally substituted with one, two        or three fluorine atoms, one or two hydroxyl groups, or one or        two —OC₁₋₂alkyl groups);

R¹⁸ is selected from the group consisting of H, Cl, F, —CN, NO₂,C₁₋₄alkyl, C₃₋₄ cycloalkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₄alkyl,—(CH₂)₀₋₁C(O)NH₂, —(CH₂)₀₋₁C(O)NHC₁₋₄alkyl, —(CH₂)₀₋₁C(O)N(C₁₋₄alkyl)₂,—(CH₂)₀₋₁C(O)OC₁₋₄alkyl, —(CH₂)₀₋₁C(O)OH, NH₂, —NHC(O)C₁₋₄alkyl,—NHS(O)₂C₁₋₄alkyl, —N(S(O)₂C₁₋₄alkyl)₂, —N(C₁₋₄alkyl)S(O)₂C₁₋₄alkyl,—N═S(O)(C₁₋₄alkyl)₂, —(CH₂)₀₋₁SC₁₋₄alkyl, —(CH₂)₀₋₁S(O)C₁₋₄alkyl,—(CH₂)₀₋₁S(O)₂C₁₋₄alkyl, —S(O)₂C₃₋₄cycloalkyl, —S(O)₂heteroaryl,—S(O)(═NH)C₁₋₄alkyl, —S(O)(═NC₁₋₄alkyl)C₁₋₄alkyl, phenyl, heteroaryl,and heterocyclyl;

-   -   wherein phenyl, heteroaryl and heterocyclyl may optionally be        substituted with one or more groups independently selected from        the group consisting of F, C₁₋₂alkyl (optionally substituted        with one, two or three fluorine atoms, one or two hydroxyl        groups, or one or two —OC₁₋₂alkyl groups), cyclopropyl,        —C(O)NH₂, —C(O)NHC₁₋₄alkyl, —C(O)N(C₁₋₄ alkyl)₂,        —C(O)OC₁₋₄alkyl, and —C(O)OH;

each of R¹⁹ and R²⁰ is independently selected from the group consistingof H and —C₁₋₄alkyl; or

R¹⁹ and R²⁰ together with the carbon atom to which they are attachedform a C₂₋₄ alkenyl moiety which may optionally be substituted with oneor two fluorine atoms;

R²¹ is selected from the group consisting of H, C₁₋₄alkyl,—C₃₋₄cycloalkyl, —(CH₂)₀₋₄C(O)C₁₋₄alkyl, —(CH₂)₀₋₄C(O)OC₁₋₄alkyl,—(CH₂)₀₋₄C(O)NH₂, —(CH₂)₀₋₄C(O)NHC₁₋₄alkyl, —(CH₂)₀₋₄C(O)N(C₁₋₄alkyl)₂,—(CH₂)₀₋₄S(O)₂C₁₋₄alkyl, and heterocyclyl;

wherein each C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₄cycloalkyl,C₃₋₆cycloalkyl, or C₅₋₆cycloalkenyl of R¹⁷, R¹⁸, R¹⁹, R²⁰, or R²¹ mayoptionally be substituted with one, two or three fluorine atoms, one ortwo hydroxyl groups, or one or two —OC₁₋₂alkyl groups;

R⁶ is independently for each occurrence selected from the groupconsisting of H, —(C₁-C₆)alkyl, —C(O)OC₁₋₄alkyl, and phenyl;

R⁴ is independently selected from the group consisting of hydrogen,—C(O)N(R⁶)₂, and —N(R⁶)₂;

-   -   D is selected from the group consisting of: phenyl, a 5- or        6-membered heteroaryl having one or two heteroatoms        independently selected from the group consisting of S, O or N,        and C₃₋₆cycloalkyl, wherein D is optionally substituted on a        carbon with one or two substituents each independently selected        from R^(D1), and, optionally substituted, on nitrogen, if        present, with one or two substituents each independently        selected from R^(D2);    -   B is fused to D such that the two atoms shared by D and B are        both carbon;    -   R^(D1) is selected from the group consisting of hydroxyl, cyano,        halogen, and, —N(R⁶)₂; and    -   R² is selected from —(C₁-C₆)alkyl and phenyl.

In some embodiments, R¹⁷ is selected from the group consisting of2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,4-triazol-3-yl, thiazol-2-yl,pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, oxazol-2-yl,oxazol-5-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-5-yl,1,3,4-thiadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl,1,2,4-triazol-2-yl, and 1,3,4-triazol-2-yl; wherein R¹⁷ may optionallybe substituted with one, two or three fluorine atoms, one or twohydroxyl groups, or one or two —OC₁₋₂alkyl groups.

In some embodiments, R¹⁷ is selected from the group consisting oftetrahydrofuran-3-yl, pyrrolidine-1-yl, piperazin-1-yl, piperidin-4-yl,piperidin-1-yl, 1,2,3,6-tetrahydropyridin-4-yl, 2,5-dihydrofuran-3-yl,piperazin-1-yl-3-one, morpholino, tetrahydropyran-2-yl, and1,2,4-oxadiazo-3-yl-5-one; wherein R¹⁷ may optionally be substitutedwith one or more hydroxyl or C₁₋₂alkyl (optionally substituted with one,two or three fluorine atoms, one or two hydroxyl groups, or one or two—OC₁₋₂alkyl groups).

In some embodiments, R¹⁸ is selected from the group consisting ofphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazol-3-yl, pyrazol-4-yl,thiazol-2-yl, 1,2,4-oxadiazol-3-yl, and 1,3,4-oxadiazol-2-yl; whereinR¹⁸ may optionally be substituted with one or more groups independentlyselected from the group consisting of F, C₁₋₂alkyl (optionallysubstituted with one, two or three fluorine atoms, one or two hydroxylgroups, or one or two —OC₁₋₂alkyl groups), cyclopropyl, —C(O)NH₂,—C(O)NHC₁₋₄alkyl, —C(O)N(C₁₋₄alkyl)₂, —C(O)OC₁₋₄alkyl, and —C(O)OH.

In some embodiments, R¹⁸ is selected from the group consisting of—(CH₂)₀₋₁i-morpholino, tetrahydropyranyl, tetrahydrofuranyl, oxiranyl,isothiazolidin-2-yl-1,1-dioxide, and —(CH₂)₀₋₁-oxazolidin-3-yl-2-one;wherein R¹⁸ R¹⁸ may optionally be substituted with one or more groupsindependently selected from the group consisting of F, C₁₋₂alkyl(optionally substituted with one, two or three fluorine atoms, one ortwo hydroxyl groups, or one or two —OC₁₋₂alkyl groups), cyclopropyl,—C(O)NH₂, —C(O)NHC₁₋₄alkyl, —C(O)N(C₁₋₄alkyl)₂, —C(O)OC₁₋₄alkyl, and—C(O)OH.

In some embodiments, R¹⁹ is —CH₃ or —CHF₂, R²⁰ is H, and the carbon towhich R¹⁹ and R²⁰ are attached has an (R)-configuration. In someembodiments, R¹⁹ is H, R²⁰ is —CH₃ or —CHF₂, and the carbon to which R¹⁹and R²⁰ are attached has an (S)-configuration.

In some embodiments, D is selected from the group consisting of:

-   -   wherein * and + represent fusion points of attachment to ring B.

In some embodiments, the present disclosure provides a compound offormula X:

or a pharmaceutically acceptable salt thereof, wherein;

X is —CH₂—, —CH(R^(X))—, —C(R^(X))₂—, —C(O)—, —NH—, —N(R^(X))—, or —O—;

Y is C, CH, C(R^(Y)), or N;

is a single bond when Y is CH, C(R^(Y)), or N; or

is a double bond when Y is C;

R¹ is L¹-Cy^(B)-L²-R²;

Cy^(B) is phenyl, a monocyclic 5-6 membered heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora bicyclic 8-10 membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein Cy^(B) issubstituted by m instances of R³;

Cy^(C) is benzo; 5-6 membered heteroarylo having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; 3-7 memberedsaturated or partially unsaturated cycloaliphatic-fused; or 3-7 memberedsaturated of partially unsaturated heterocyclo having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein whenCy^(C) is heterocyclo or heteroarylo, said heteroatoms may occur at anyposition within Cy^(C); and wherein in each case Cy^(C) is substitutedby n instances of R⁴;

L¹ is a covalent bond or —C(O)—;

L² is a covalent bond, or a C₁₋₄ bivalent saturated or unsaturated,straight or branched hydrocarbon chain wherein one or two methyleneunits of the chain are optionally and independently replaced by

—CH(R^(L))—, —C(R^(L))₂—, C₃₋₅cycloalkylene, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,

—O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O)₂—;

R² is hydrogen, R^(A), or R^(B), and when R² is R^(B), R² is substitutedby q instances of R^(C);

each instance of R³, R⁴, R^(X), R^(Y), and R^(L) is independently R^(A)or R^(B), and is substituted by r instances of R^(C);

each instance of R⁵ is independently R^(A) or R^(B), and is substitutedby r instances of R^(C); or two instances of R⁵ are taken together withtheir intervening atoms to form a 3-6 membered carbocyclic fused ring ora 3-6 membered heterocyclic fused ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur;

each instance of R^(A) is independently oxo, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —O C(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, or —N(R)S(O)₂R;

each instance of R^(B) is independently C₁₋₆ aliphatic; phenyl; a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated carbocyclic ring; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; or a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur;

each instance of R^(C) is independently oxo, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —OS(O)₂F, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, oran optionally substituted group selected from C₁₋₆ aliphatic, phenyl, a3-7 membered saturated or partially unsaturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur;

each R is independently hydrogen, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or:

two R groups on the same nitrogen are taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur;

each of b and c is independently 0 or 1; and

each of a, m, n, q, and r is independently 0, 1, 2, 3, or 4;

wherein the compound is not

In some embodiments, a compound disclosed herein is of the one offormulas:

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, R¹,R⁴, R⁵, a, b, c, and n are as defined in embodiments and classes andsubclasses herein.

In some embodiments, Cy^(B) is selected from the group consisting of:

wherein Cy^(B) is substituted by m instances of R³.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),X, Y, L², R², R³, R⁵, a, b, and c, are as defined in embodiments andclasses and subclasses herein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),Y, R¹, R⁵, a, b, and c, are as defined in embodiments and classes andsubclasses herein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),X, Y, R¹, R⁵, a, b, and c, are as defined in embodiments and classes andsubclasses herein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),Y, R¹, R⁵, and a are as defined in embodiments and classes andsubclasses herein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),Y, and R¹ are as defined in embodiments and classes and subclassesherein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C)and R¹ are as defined in embodiments and classes and subclasses herein.

In some embodiments, variable a is 2, or a pharmaceutically acceptablesalt thereof.

In some embodiments, two instances of R⁵ are taken together with theirintervening atoms to form a 3-6 membered carbocyclic fused ring or a 3-6membered heterocyclic fused ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present disclosure provides a compound of theformula:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C)and R¹ are as defined in embodiments and classes and subclasses herein.

In some embodiments, the present disclosure provides a compound of theformula:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C)and R¹ are as defined in embodiments and classes and subclasses herein.

In some embodiments, the present disclosure provides a compound of oneof formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),X, L² and R² are as defined in embodiments and classes and subclassesherein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of X, L²,R², R³, R⁴, and n are as defined in embodiments and classes andsubclasses herein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of X, L²,R², R³, R⁴, and n are as defined in embodiments and classes andsubclasses herein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of X, L²,R², R³, R⁴, and n are as defined in embodiments and classes andsubclasses herein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of L², R²,R³, R⁴, and n are as defined in embodiments and classes and subclassesherein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of L², R²,R³, R⁴, and n are as defined in embodiments and classes and subclassesherein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of L², R²,R³, R⁴, and n are as defined in embodiments and classes and subclassesherein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of L², R²,R³, R⁴, and n are as defined in embodiments and classes and subclassesherein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of L², R²,R³, R⁴, and n are as defined in embodiments and classes and subclassesherein.

In some embodiments, a compound disclosed herein is of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of L², R²,R³, R⁴, and n are as defined in embodiments and classes and subclassesherein.

In some embodiments, at least one instance of R³

is —CH₃, —CHF₂, —CH₂OH, —CH(CH₃)OH, or cyclopropyl.

In some embodiments, X is —CH₂—, or a pharmaceutically acceptable saltthereof.

In some embodiments, X is —O—, or a pharmaceutically acceptable saltthereof.

In some embodiments, Cy^(C) is benzo, or a pharmaceutically acceptablesalt thereof.

In some embodiments, Cy^(C) is 5-6 membered heteroarylo having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur, ora pharmaceutically acceptable salt thereof.

In some embodiments, Y is —N—, or a pharmaceutically acceptable saltthereof.

In some embodiments, Y is —CH₂—, or a pharmaceutically acceptable saltthereof.

In some embodiments, L is a covalent bond, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, L¹ is —C(O)—, or a pharmaceutically acceptable saltthereof.

In some embodiments, L² is a covalent bond, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, L² is —S—, or a pharmaceutically acceptable saltthereof.

In some embodiments, L² is —O—, or a pharmaceutically acceptable saltthereof.

In some embodiments, L² is —C(O)—, or a pharmaceutically acceptable saltthereof.

In some embodiments, L² is C₁₋₃ aliphatic, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, n is 1, 2, 3, or 4, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, n is 0, or a pharmaceutically acceptable saltthereof.

In some embodiments, at least one instance of R⁴ is fluoro, or apharmaceutically acceptable salt thereof.

In some embodiments, R² is C₁₋₆ aliphatic; phenyl; a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 3-7 membered saturated or partially unsaturatedcarbocyclic ring; a 3-7 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturatedor partially unsaturated bicyclic heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein R² is substituted by q instances of R^(C), or a pharmaceuticallyacceptable salt thereof.

In some embodiments, R² is C₁₋₆ aliphatic substituted with q instancesof R^(C), or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is phenyl substituted with q instances of R^(C),or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is an 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur substituted with q instances of R^(C), or a pharmaceuticallyacceptable salt thereof; a 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur

In some embodiments, R² is a 3-7 membered saturated or partiallyunsaturated carbocyclic ring substituted with q instances of R^(C), or apharmaceutically acceptable salt thereof.

In some embodiments, R² is a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, substitutedwith q instances of R^(C), or a pharmaceutically acceptable saltthereof.

In some embodiments, R² is 7-12 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, substitutedwith q instances of R^(C), or a pharmaceutically acceptable saltthereof.

In some embodiments, R² is:

isopropyl, ethyl, or methyl, each of which is substituted with qinstances of R^(C), or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is:

each of which is substituted with q instances of R^(C), or apharmaceutically acceptable salt thereof.

In some embodiments, R² is:

each of which is substituted with q instances of R^(C), or apharmaceutically acceptable salt thereof.

In some embodiments, R² is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound offormula XI:

or a pharmaceutically acceptable salt thereof, wherein;

X is —CH₂—, —CH(R^(X))—, —C(R^(X))₂—, —C(O)—, —NH—, —N(R^(X))—, or —O—;

Y is CH, C(R^(Y)), or N;

Z is —CH₂—, —CH(R^(Z))—, —C(R^(Z))₂—, —NH—, —N(R^(Z))—, or —O—;

Cy^(B) is phenyl, a monocyclic 5-6 membered heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora bicyclic 8-10 membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein Cy^(B) issubstituted by m instances of R³;

Cy^(C) is benzo; 5-6 membered heteroarylo having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; 3-7 memberedsaturated or partially unsaturated cycloaliphatic-fused; or 3-7 memberedsaturated of partially unsaturated heterocyclo having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein whenCy^(C) is heterocyclo or heteroarylo, said heteroatoms may occur at anyposition within Cy^(C); and wherein in each case Cy^(C) is substitutedby n instances of R⁴;

L² is a covalent bond, or a C₁₋₄ bivalent saturated or unsaturated,straight or branched hydrocarbon chain wherein one or two methyleneunits of the chain are optionally and independently replaced by—CH(R^(L))—, —C(R^(L))₂—, C₃₋₅ cycloalkylene, —N(R)—, —N(R)C(O)—,—C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—,—S—, —S(O)—, or —S(O)₂—;

R² is hydrogen, R^(A), or R^(B), and when R² is R^(B), R² is substitutedby q instances of R^(C);

each instance of R³, R⁴, R^(X), R^(Y), R^(Z), and R^(L) is independentlyR^(A) or R^(B), and is substituted by r instances of R^(C);

each instance of R⁵ is independently R^(A) or R^(B), and is substitutedby r instances of R^(C); or two instances of R⁵ are taken together withtheir intervening atoms to form a 3-6 membered carbocyclic fused ring ora 3-6 membered heterocyclic fused ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur;

each instance of R^(A) is independently oxo, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, or —N(R)S(O)₂R;

each instance of R^(B) is independently C₁₋₆ aliphatic; phenyl; a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated carbocyclic ring; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; or a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur;

each instance of R^(C) is independently oxo, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 3-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur;

each R is independently hydrogen, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or:

two R groups on the same nitrogen are taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur;

each of b and c is independently 0 or 1; and

each of a, m, n, q, and r is independently 0, 1, 2, 3, or 4

In some embodiments, the present disclosure provides a compound offormula XI of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),Cy^(B), X, Y, Z, R³, L², and R² are as defined in embodiments andclasses and subclasses herein.

In some embodiments, the present disclosure provides a compound offormula XI of one of formulas:

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(C),R³, L², and R² are as defined in embodiments and classes and subclassesherein.

Examples of compounds of the present disclosure include those listed inthe Tables and exemplification herein, or a pharmaceutically acceptablesalt, stereoisomer, or mixture of stereoisomers thereof. In someembodiments, the present disclosure comprises a compound selected fromthose depicted in Table 1, or a pharmaceutically acceptable salt,stereoisomer, or mixture of stereoisomers thereof:

TABLE 1 Representative Compounds of the disclosure. Example Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

Compounds or compositions of the disclosure can be useful inapplications that benefit from inhibition of SHP2 phosphatase enzymes.For example, inhibition of SHP2 phosphatase may offer a therapeuticapproach for the treatment of cancer. (See, e.g., Y.-N. P. Chen et al.,in Nature, 2016, doi: 10.1038/nature18621; and references cited therein;each of which hereby incorporated by reference in its entirety.)Inhibition of SHP2 phosphatase also has been found to ameliorate thepathogensis of systemic lupus erythematosus. (See, e.g., J. Wang et al.,in J. Clin. Invest. 2016, 126, 2077-2092; and references cited therein;each of which hereby incorporated by reference in its entirety.)

In some embodiments, compounds or compositions of the disclosure can beuseful in suppressing tumor cell growth. In some embodiments, compoundsor compositions of the disclosure can be useful in ameliorating thepathogenesis of systemic lupus erythematosus. In some embodiments,compounds or compositions of the disclosure can be useful in thetreatment of various other disorders, including neurofibromatosis (e.g.neurofibromatosis type 1 (NF1), Noonan syndrome (NS)), diabetes,neuroblastoma, melanoma (see. Hill et al, Mol. Cancer Res. 2019, 17,583-593), juvenile leukemia, juvenile myelomonocytic leukemia (JMML, seeYu et al, Mol. Cancer Ther. 2013, 12, 1738-1748), chronic myelomonocyticleukemia, acute myeloid leukemia, HER2-positive breast cancer (see Hu etal, Oncol Rep. 2014; 32(1):205-12; and Zhao et al, Oncogene, doi:10.1038/s41388-018-0574-8), triple-negative breast cancer (seeSausgruber et al, Oncogene, 2015, 34, 2272-2278), ductal carcinoma ofthe breast, invasive ductal carcinoma of the breast, non-small cell lungcancer (including adenocarcinoma of the lung, see Nichols et al, 2018,Nat. Cell Biol. 20, 1064-1073; and Mainardi et al, 2018, Nat Med. 24(4):512-517), colorectal cancer, esophageal cancer (Qi et al, 2017, Int. J.Mol. Sci. 18, 134), gastric cancer, squamous-cell carcinoma of the headand neck (SCCHN), neutropenia (Kostmann's syndrome), ovarian cancer (seeSun et al, 2019, Am J Cancer Res.; 9(1):145-159), anFGFR1-amplified/mutant cancer (e.g. FGFR1-amplified or mutant breastcancer, lung cancer, or prostate cancer), an FGFR2-amplified cancer(e.g. FGFR2-amplified gastric cancer), an FGFR2-fusion/mutant cancer(e.g. FGFR2-fusion/mutant cholangiocarcinoma), or an FGFR3-fusion/mutantcancer (e.g. FGFR3-fusion or mutant bladder cancer). In someembodiments, the disorder treated is a proliferative disorder. In someembodiments, the disorder treated is a solid tumor. In some embodiments,the disorder treated is a neurofibromatosis (e.g. neurofibromatosis type1 (NF1), Noonan syndrome (NS)). In some embodiments, the disordertreated is diabetes. In some embodiments, the disorder treated is aneuroblastoma. In some embodiments, the disorder treated is melanoma. Insome embodiments, the disorder treated is a hematological cancer. Insome embodiments, the disorder treated is a juvenile leukemia. In someembodiments, the disorder treated is a juvenile myelomonocytic leukemia(JMML). In some embodiments, the disorder treated is a chronicmyelomonocytic leukemia. In some embodiments, the disorder treated is anacute myeloid leukemia. In some embodiments, the disorder treated is abreast cancer. In some embodiments, the disorder treated is aHER2-positive breast cancer. In some embodiments, the disorder treatedis a triple-negative breast cancer. In some embodiments, the disordertreated is a ductal carcinoma of the breast. In some embodiments, thedisorder treated is an invasive ductal carcinoma of the breast. In someembodiments, the disorder treated is a non-small cell lung cancer(including adenocarcinoma of the lung). In some embodiments, thedisorder treated is a colorectal cancer. In some embodiments, thedisorder treated is an esophageal cancer. In some embodiments, thedisorder treated is a gastric cancer. In some embodiments, the disordertreated is a squamous-cell carcinoma of the head and neck (SCCHN). Insome embodiments, the disorder treated is a neutropenia (e.g. Kostmann'ssyndrome). In some embodiments, the disorder treated is an ovariancancer. In some embodiments, the disorder treated is anFGFR1-amplified/mutant cancer (e.g. FGFR1-amplified or mutant breastcancer, lung cancer, or prostate cancer). In some embodiments, thedisorder treated is an FGFR2-amplified cancer (e.g. FGFR2-amplifiedgastric cancer). In some embodiments, the disorder treated is anFGFR2-fusion/mutant cancer (e.g. FGFR2-fusion/mutantcholangiocarcinoma). In some embodiments, the disorder treated is or anFGFR3-fusion/mutant cancer (e.g. FGFR3-fusion or mutant bladder cancer).

In some embodiments, compounds or compositions of the disclosure can beused in combination with other treatments and/or cancer therapies. Forexample, compounds or compositions of the disclosure can be used incombination with, but are not limited to, antibodies, antibody-drugconjugates, kinase inhibitors, immunomodulators, and histone deacetylaseinhibitors. The compounds or compositions of the disclosure can also beused in combination with other treatments and/or cancer therapies asdisclosed in WO 2015/107495; and references cited therein; each of whichis hereby incorporated by reference in its entirety.

For example, the compounds disclosed herein (or pharmaceuticalcompositions containing them) can be used in the treatment of one ormore of the diseases mentioned herein, alone or in combination withanother therapeutic agent. For example, in some embodiments, a providedcompound can be used in combination with one or more of the followingagents, or a pharmaceutically acceptable salt thereof: BCR-ABLinhibitors: e.g. imatinib, inilotinib, nilotinib, dasatinib, bosutinib,ponatinib, bafetinib, danusertib, saracatinib, PF03814735; ALKinhibitors (see Dardaei et al, 2018, Nat Med.; 24(4):512-517): e.g.crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrecinib,lorlatinib; BRAF inhibitors (see Prahallad et al, 2015, Cell Rep. 12,1978-1985): e.g. vemurafenib, dabrafenib; FGFR inhibitors: e.g.infigratinib, dovitinib, erdafitinib, BLU-554, AZD4547; FLT3 inhibitors:e.g. sunitinib, midostaurin, tanutinib, sorafenib, lestaurtinib,quizartinib, and crenolanib; MEK Inhibitors (see Fedele et al, 2018,BioRxiv 307876; Torres-Ayuso et al, 2018, Cancer Discov. 8, 1210-1212;and Wong et al, 2016, Oncotarget. 2016 Oct. 4; 7(40): 65676-65695): e.g.trametinib, cobimetinib, binimetinib, selumetinib; ERK inhibitors: e.g.ulixertinib, MK-8353, LY-3214996; VEGF receptor inhibitors: e.g.bevacizumab, axitinib, aflibercept, brivanib, motesanib, pasireotide,sorafenib; Tyrosine kinase inhibitors: e.g. erlotinib, linifanib,sunitinib, pazopanib; Epidermal growth factor receptor (EGFR)inhibitors: gefitnib, osimertinib, cetuximab, panitumumab; HER2 receptorinhibitors: e.g. trastuzumab, neratinib, lapatinib, lapatinib; METinhibitors: e.g. crizotinib, cabozantinib; CD20 antibodies: e.g.rituximab, tositumomab, ofatumumab; DNA Synthesis inhibitors: e.g.capecitabine, gemcitabine, nelarabine, hydroxycarbamide; Antineoplasticagents: e.g. oxaliplatin, cisplatin; HER dimerization inhibitors: e.g.pertuzumab; Human Granulocyte colony-stimulating factor (G-CSF)modulators: e.g. filgrastim; Immunomodulators: e.g. afutuzumab,lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: e.g.dacetuzumab; Pro-apoptotic receptor agonists (PARAs): e.g. dulanermin;Heat Shock Protein (HSP) inhibitors: e.g. tanespimycin(17-allylamino-17-desmethoxygeldanamycin); Hedgehog antagonists: e.g.vismodegib; Proteasome inhibitors: e.g. bortezomib; PI3K inhibitors:e.g. pictilisib, dactolisib, buparlisib, taselisib, idelalisib,duvelisib, umbralisib; Phospholipase A2 inhibitors: e.g. anagrelide;BCL-2 inhibitors: e.g. venetoclax; Aromatase inhibitors: exemestane,letrozole, anastrozole, faslodex, tamoxifen; Topoisomerase I inhibitors:e.g. irinotecan, topotecan; Topoisomerase II inhibitors: e.g. etoposide,teniposide; mTOR inhibitors: e.g. temsirolimus, ridaforolimus,everolimus, sirolimus; Osteoclastic bone resorption inhibitors: e.g.zoledronic acid; CD33 Antibody Drug Conjugates: e.g. gemtuzumabozogamicin; CD22 Antibody Drug Conjugates: e.g. inotuzumab ozogamicin;CD20 Antibody Drug Conjugates: e.g. ibritumomab tiuxetan; Somatostainanalogs: e.g. octreotide; Interleukin-11 (IL-11): e.g. oprelvekin;Synthetic erythropoietin: e.g. darbepoetin alfa; Receptor Activator forNuclear Factor κ B (RANK) inhibitors: e.g. denosumab; Thrombopoietinmimetic peptides: e.g. romiplostim; Cell growth stimulators: e.g.palifermin; Anti-Insulin-like Growth Factor-1 receptor (IGF-1R)antibodies: e.g. figitumumab; Anti-CSl antibodies: e.g. elotuzumab; CD52antibodies: e.g. alemtuzumab; CTLA-4 inhibitors: e.g. tremelimumab,ipilimumab; PD1 inhibitors: e.g. nivolumab, pembrolizumab; animmunoadhesin; e.g. pidilizumab, AMP-224; PDL1 inhibitors: e.g.MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C, orMDX-1105; LAG-3 inhibitors: e.g. BMS-986016; GITR agonists; GITR fusionproteins and anti-GITR antibodies; Histone deacetylase inhibitors (HDI):e.g. voninostat; Anti-CTLA4 antibodies: e.g. tremelimumab, ipilimumab;Alkylating agents: e.g. temozolomide, dactinomycin, melphalan,altretamine carmustine, bendamustine, busulfan, carboplatin, lomustine,cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretamine,ifosfamide, procarbazine, mechlorethamine, mustine and mechloroethamine,streptozocin, thiotepa; Biologic response modifiers: e.g. bacilluscalmette-guerin, denileukin diftitox; Anti-tumor antibiotics: e.g.doxorubicin, bleomycin, daunorubicin, daunorubicin liposomal,mitoxantrone, epirubicin, idarubicin, mitomycin C; Anti-microtubuleagents: e.g. estramustine; Cathepsin K inhibitors: e.g. odanacatib;Epothilone analogs: e.g. ixabepilone; TpoR agonists: e.g. eltrombopag;Anti-mitotic agents: e.g. docetaxel; Adrenal steroid inhibitors: e.g.aminoglutethimide; Anti-androgens: e.g. nilutamide; Androgen Receptorinhibitors: e.g. enzalutamide, abiraterone acetate, orteronel,galeterone, and seviteronel, bicalutamide, flutamide; Androgens: e.g.fluoxymesterone; CDK1 inhibitors: e.g. alvocidib, palbociclib,ribociclib, trilaciclib, abemaciclib; Gonadotropin-releasing hormone(GnRH) receptor agonists: e.g. leuprolide or leuprolide acetate; Taxaneanti-neoplastic agents: e.g. cabazitaxel, larotaxel; 5-HTla receptoragonists: e.g. xaliproden; HPV vaccines: e.g. Cervarix® sold byGlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: e.g.deferasirox; Anti-metabolites: e.g. claribine, 5-fluorouracil,6-thioguanine, pemetrexed, cytarabine, cytarabine liposomal, decitabine,hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate,pentostatin; Bisphosphonates: e.g. pamidronate; Demethylating agents:e.g. 5-azacitidine, decitabine; Anti-tumor Plant Alkaloids: e.g.paclitaxel protein-bound; vinblastine, vincristine, vinorelbine,paclitaxel; Retinoids: e.g. alitretinoin, tretinoin, isotretinoin,bexarotene; Glucocorticosteroids: e.g. hydrocortisone, dexamethasone,prednisolone, prednisone, methylprednisolone; Cytokines: e.g.interleukin-2, interleukin-11 (oprevelkin), alpha interferon alfa(IFN-alpha); estrogen receptor downregulators: fulvestrant;Anti-estrogens: e.g. tamoxifen, toremifene; Selective estrogen receptormodulators (SERMs): e.g. raloxifene; Luteinizing hormone releasinghormone (LHRH) agonists: e.g. goserelin; Progesterones: e.g. megestrol;cytotoxic agents: arsenic trioxide, asparaginase (also known asL-asparaginase, Erwinia L-asparaginase; Anti-nausea drugs: e.g. NK-1receptor antagonists (e.g. casopitant); Cytoprotective agents: e.g.amifostine, leucovorin; and Immune checkpoint inhibitors. The term“immune checkpoints” refers to a group of molecules on the cell surfaceof CD4 and CD8 T cells. Immune checkpoint molecules include, but are notlimited to, Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte Antigen 4(CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3. Immunotherapeuticagents which can act as immune checkpoint inhibitors useful in themethods of the present disclosure, include, but are not limited to,inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT,LAIR1, CD 160, 2B4 and/or TGFR beta.

The compounds described herein can function as allosteric inhibitors andblock the activation of SHP2 by targeting the auto-inhibitedconformation of SHP2.

The compounds described herein can also inhibit SHP2 function throughincorporation into agents that catalyze the destruction of SHP2. Forexample, the compounds can be incorporated into proteolysis targetingchimeras (PROTACs). A PROTAC is a bifunctional molecule, with oneportion capable of engaging an E3 ubiquitin ligase, and the otherportion having the ability to bind to a target protein meant fordegradation by the cellular protein quality control machinery.Recruitment of the target protein to the specific E3 ligase results inits tagging for destruction (i.e., ubiquitination) and subsequentdegradation by the proteasome. Any E3 ligase can be used. The portion ofthe PROTAC that engages the E3 ligase is connected to the portion of thePROTAC that engages the target protein via a linker which consists of avariable chain of atoms. Recruitment of SHP2 to the E3 ligase will thusresult in the destruction of the SHP2 protein. The variable chain ofatoms can include, for example, rings, heteroatoms, and/or repeatingpolymeric units. It can be rigid or flexible. It can be attached to thetwo portions described above using standard techniques.

The compounds described herein can be linked to one end of a variablechain, while the other end of the variable chain can be bound to the E3ligase. Recruitment of SHP2 to the ligase will thus result in thedestruction of the SHP2 protein.

In some embodiments, compounds or compositions of the disclosure can beused in combination with an antibody. In some embodiments, compounds orcompositions of the disclosure can be used in combination with anantibody-drug conjugate. In some embodiments, compounds or compositionsof the disclosure can be used in combination with a kinase inhibitor. Insome embodiments, compounds or compositions of the disclosure can beused in combination with an immunomodulator. In some embodiments,compounds or compositions of the disclosure can be used in combinationwith a histone deacetylase inhibitor.

In some embodiments, the present disclosure provides a method oftreating a SHP2-mediated disorder comprising administering to a subjectin need thereof a compound described herein, wherein the disorder isselected from those described in WO2019051084A1, hereby incorporated byreference in its entirety.

In some embodiments, the present disclosure provides a method oftreating a SHP2-mediated disorder comprising administering to a subjectin need thereof a compound described herein together with an additionaltherapeutic agent, wherein the additional therapeutic agent is not aSHP2 inhibitor, and is selected from those described in WO2019051084A1,hereby incorporated by reference in its entirety.

In some embodiments, a disclosed compound can be administered to asubject in need of treatment at dosages ranging from about 0.0001 mg toabout 100 mg/kg body weight of the subject to be treated per day, suchas from about 1.0 to 10 mg/kg. However, additional variations are withinthe scope of the disclosure.

A disclosed compound can be administered alone or in combination withpharmaceutically acceptable carriers, such as diluents, fillers, aqueoussolution, and even organic solvents. The compound and/or compositions ofthe disclosure can be administered as a tablet, powder, lozenge, syrup,injectable solution, and the like. Additional ingredients, such asflavoring, binder, excipients, and the like are within the scope of thedisclosure.

In some embodiments, pharmaceutically acceptable compositions cancontain a disclosed compound and/or a pharmaceutically acceptable saltthereof at a concentration ranging from about 0.01 to about 90 wt %,about 0.01 to about 80 wt %, about 0.01 to about 70 wt %, about 0.01 toabout 60 wt %, about 0.01 to about 50 wt %, about 0.01 to about 40 wt %,about 0.01 to about 30 wt %, about 0.01 to about 20 wt %, about 0.01 toabout 2.0 wt %, about 0.01 to about 1 wt %, about 0.05 to about 0.5 wt%, about 1 to about 30 wt %, or about 1 to about 20 wt %. Thecomposition can be formulated as a solution, suspension, ointment, or acapsule, and the like. The pharmaceutical composition can be prepared asan aqueous solution and can contain additional components, such aspreservatives, buffers, tonicity agents, antioxidants, stabilizers,viscosity-modifying ingredients and the like.

In some embodiments, the present disclosure provides for the use ofpharmaceutical compositions and/or medicaments comprised of a disclosedcompound or a pharmaceutically acceptable salt thereof, in a method oftreating a disease state, and/or condition caused by or related to SHP2phosphatase. For example, provided herein are methods of treatingsubjects in need thereof (e.g., subjects suffering from cancer (e.g.,leukemia, breast, lung and/or colorectal cancer) an effective amount ofa disclosed compound, and optionally an effective amount of anadditional compound (e.g., therapeutic agent) such as disclosed herein.

In some embodiments, the method of treatment comprises the steps of: i)identifying a subject in need of such treatment; (ii) providing adisclosed compound, e.g., of Formula Ia, Formula Ib, Formula II, FormulaIII, Formula X, or Formula XI, or a pharmaceutically acceptable saltthereof, and (iii) administering said disclosed compound, e.g., ofFormula Ia, Formula Ib, Formula II, Formula III, Formula X, or FormulaXI in a therapeutically effective amount to treat, suppress and/orprevent the disease state or condition in a subject in need of suchtreatment.

In some embodiments, the method of treatment comprises the steps of: i)identifying a subject in need of such treatment; (ii) providing acomposition comprising a disclosed compound, e.g., of Formula Ia,Formula Ib, Formula II, Formula III, Formula X, or Formula XI, or apharmaceutically acceptable salt thereof; and (iii) administering saidcomposition in a therapeutically effective amount to treat, suppressand/or prevent the disease state or condition in a subject in need ofsuch treatment.

In some embodiments, the subject is an animal. Animals include allmembers of the animal kingdom, but are not limited to humans, mice,rats, cats, monkeys, dogs, horses, and swine. In some embodiments, thesubject is a human. In some embodiments, the subject is a mouse, a rat,a cat, a monkey, a dog, a horse, or a pig.

In some embodiments, a compound or composition of the disclosure isadministered orally, intravenously, by inhalation, intranasally,intraocularly, topically, subcutaneously, rectally, intravaginally, orintrathecally. In some embodiments, the compound or composition isadministered orally. In some embodiments, the compound or composition isadministered intravenously.

In some embodiments, the methods comprise administering to the subjectan effective amount of a disclosed compound, e.g., of Formula Ia,Formula Ib, Formula II, Formula III, Formula X, or Formula XI, or apharmaceutically acceptable salt thereof; or a composition comprising adisclosed compound, e.g., of Formula Ia, Formula Ib, Formula II, FormulaIII, Formula X, or Formula XI, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well-known to those skilled inthe art, and include, e.g., adjuvants, diluents, excipients, fillers,lubricants and vehicles. In some embodiments, the carrier is a diluent,adjuvant, excipient, or vehicle. In some embodiments, the carrier is adiluent, adjuvant, or excipient. In some embodiments, the carrier is adiluent or adjuvant. In some embodiments, the carrier is an excipient.Often, the pharmaceutically acceptable carrier is chemically inerttoward the active compounds and is non-toxic under the conditions ofuse. Examples of pharmaceutically acceptable carriers may include, e.g.,water or saline solution, polymers such as polyethylene glycol,carbohydrates and derivatives thereof, oils, fatty acids, or alcohols.Non-limiting examples of oils as pharmaceutical carriers include oils ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalcarriers may also be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.Other examples of suitable pharmaceutical carriers are described ine.g., Remington's: The Science and Practice of Pharmacy, 22nd Ed.(Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); ModernPharmaceutics, 5^(th) Ed. (Alexander T. Florence, Juergen Siepmann, CRCPress (2009)); Handbook of Pharmaceutical Excipients, 7^(th) Ed. (Rowe,Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds.,Pharmaceutical Press (2012)) (each of which hereby incorporated byreference in its entirety).

In some embodiments, the method of treatment, prevention and/orsuppression of a condition related to SHP2 phosphatase comprises thesteps of: i) identifying a subject in need of such treatment; (ii)providing a disclosed compound, e.g., of Formula Ia, Formula Ib, FormulaII, Formula III, Formula X, or Formula XI, or a pharmaceuticallyacceptable salt thereof, or a composition comprising a disclosedcompound, e.g., of Formula Ia, Formula Ib, Formula II, Formula III,Formula X, or Formula XI, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier; and (iii) administering saidcompound or composition in a therapeutically effective amount to treat,prevent and/or suppress the disease state or condition related to SHP2phosphatase in a subject in need of such treatment.

In some embodiments, the compounds of the disclosure are formulated intopharmaceutical compositions for administration to subjects in abiologically compatible form suitable for administration in vivo.According to another aspect, the present disclosure provides apharmaceutical composition comprising a disclosed compound, e.g., ofFormula Ia, Formula Ib, Formula II, Formula III, Formula X, or FormulaXI, in admixture with a pharmaceutically acceptable diluent and/orcarrier. The pharmaceutically-acceptable carrier is “acceptable” in thesense of being compatible with the other ingredients of the compositionand not deleterious to the recipient thereof. Thepharmaceutically-acceptable carriers employed herein may be selectedfrom various organic or inorganic materials that are used as materialsfor pharmaceutical formulations and which are incorporated as analgesicagents, buffers, binders, disintegrants, diluents, emulsifiers,excipients, extenders, glidants, solubilizers, stabilizers, suspendingagents, tonicity agents, vehicles and viscosity-increasing agents.Pharmaceutical additives, such as antioxidants, aromatics, colorants,flavor-improving agents, preservatives, and sweeteners, may also beadded. Examples of acceptable pharmaceutical carriers includecarboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic,lactose, magnesium stearate, methyl cellulose, powders, saline, sodiumalginate, sucrose, starch, talc and water, among others. In someembodiments, the term “pharmaceutically acceptable” means approved by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia for use inanimals, and more particularly in humans.

Surfactants such as, e.g., detergents, are also suitable for use in theformulations. Specific examples of surfactants includepolyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin orsodium carboxymethylcellulose; or acrylic derivatives, such asmethacrylates and others, anionic surfactants, such as alkalinestearates, in particular sodium, potassium or ammonium stearate; calciumstearate or triethanolamine stearate; alkyl sulfates, in particularsodium lauryl sufate and sodium cetyl sulfate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids, in particular those derived from coconut oil, cationicsurfactants, such as water-soluble quaternary ammonium salts of formulaN⁺R′R″R′″R″″Y⁻, in which the R radicals are identical or differentoptionally hydroxylated hydrocarbon radicals and Y⁻ is an anion of astrong acid, such as halide, sulfate and sulfonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used, amine salts of formula N⁺R′R″R′″, in which the R radicalsare identical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used, non-ionic surfactants, such as optionallypolyoxyethylenated esters of sorbitan, in particular Polysorbate 80, orpolyoxyethylenated alkyl ethers; polyethylene glycol stearate,polyoxyethylenated derivatives of castor oil, polyglycerol esters,polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids orcopolymers of ethylene oxide and of propylene oxide, amphotericsurfactants, such as substituted lauryl compounds of betaine.

When administered to a subject, a disclosed compound, e.g., of FormulaIa, Formula Ib, Formula II, Formula III, Formula X, or Formula XI, andpharmaceutically acceptable carriers can be sterile. Suitablepharmaceutical carriers may also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300,water, ethanol, polysorbate 20, and the like. The present compositions,if desired, may also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents.

The pharmaceutical formulations of the present disclosure are preparedby methods well-known in the pharmaceutical arts. Optionally, one ormore accessory ingredients (e.g., buffers, flavoring agents, surfaceactive agents, and the like) also are added. The choice of carrier isdetermined by the solubility and chemical nature of the compounds,chosen route of administration and standard pharmaceutical practice.

Additionally, the compounds and/or compositions of the presentdisclosure are administered to a human or animal subject by knownprocedures including oral administration, sublingual or buccaladministration. In some embodiments, the compound and/or composition isadministered orally.

For oral administration, a formulation of the compounds of thedisclosure may be presented in dosage forms such as capsules, tablets,powders, granules, or as a suspension or solution. Capsule formulationsmay be gelatin, soft-gel or solid. Tablets and capsule formulations mayfurther contain one or more adjuvants, binders, diluents, disintegrants,excipients, fillers, or lubricants, each of which are known in the art.Examples of such include carbohydrates such as lactose or sucrose,dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol,cellulose or derivatives thereof, microcrystalline cellulose, gelatin,stearates, silicon dioxide, talc, sodium starch glycolate, acacia,flavoring agents, preservatives, buffering agents, disintegrants, andcolorants. Orally administered compositions may contain one or moreoptional agents such as, e.g., sweetening agents such as fructose,aspartame or saccharin; flavoring agents such as peppermint, oil ofwintergreen, or cherry; coloring agents; and preservative agents, toprovide a pharmaceutically palatable preparation.

In some embodiments, the composition is in unit dose form such as atablet, capsule or single-dose vial. Suitable unit doses, i.e.,therapeutically effective amounts, may be determined during clinicaltrials designed appropriately for each of the conditions for whichadministration of a chosen compound is indicated and will, of course,vary depending on the desired clinical endpoint.

In accordance with the methods of the present disclosure, the compoundsof the disclosure are administered to the subject in a therapeuticallyeffective amount, e.g., to reduce or ameliorate symptoms related to SHP2phosphatase activity in the subject. This amount is readily determinedby the skilled artisan, based upon known procedures, including analysisof titration curves established in vivo and methods and assays disclosedherein.

In some embodiments, the methods comprise administration of atherapeutically effective dosage of the compounds of the disclosure. Insome embodiments, the therapeutically effective dosage is at least about0.0001 mg/kg body weight, at least about 0.001 mg/kg body weight, atleast about 0.01 mg/kg body weight, at least about 0.05 mg/kg bodyweight, at least about 0.1 mg/kg body weight, at least about 0.25 mg/kgbody weight, at least about 0.3 mg/kg body weight, at least about 0.5mg/kg body weight, at least about 0.75 mg/kg body weight, at least about1 mg/kg body weight, at least about 2 mg/kg body weight, at least about3 mg/kg body weight, at least about 4 mg/kg body weight, at least about5 mg/kg body weight, at least about 6 mg/kg body weight, at least about7 mg/kg body weight, at least about 8 mg/kg body weight, at least about9 mg/kg body weight, at least about 10 mg/kg body weight, at least about15 mg/kg body weight, at least about 20 mg/kg body weight, at leastabout 25 mg/kg body weight, at least about 30 mg/kg body weight, atleast about 40 mg/kg body weight, at least about 50 mg/kg body weight,at least about 75 mg/kg body weight, at least about 100 mg/kg bodyweight, at least about 200 mg/kg body weight, at least about 250 mg/kgbody weight, at least about 300 mg/kg body weight, at least about 350mg/kg body weight, at least about 400 mg/kg body weight, at least about450 mg/kg body weight, at least about 500 mg/kg body weight, at leastabout 550 mg/kg body weight, at least about 600 mg/kg body weight, atleast about 650 mg/kg body weight, at least about 700 mg/kg body weight,at least about 750 mg/kg body weight, at least about 800 mg/kg bodyweight, at least about 900 mg/kg body weight, or at least about 1000mg/kg body weight. It will be recognized that any of the dosages listedherein may constitute an upper or lower dosage range, and may becombined with any other dosage to constitute a dosage range comprisingan upper and lower limit.

In some embodiments, the therapeutically effective dosage is in therange of about 0.1 mg to about 10 mg/kg body weight, about 0.1 mg toabout 6 mg/kg body weight, about 0.1 mg to about 4 mg/kg body weight, orabout 0.1 mg to about 2 mg/kg body weight.

In some embodiments the therapeutically effective dosage is in the rangeof about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg,about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg orabout 40 to 80 mg.

In some embodiments, the methods comprise a single dosage oradministration (e.g., as a single injection or deposition).Alternatively, the methods comprise administration once daily, twicedaily, three times daily or four times daily to a subject in needthereof for a period of from about 2 to about 28 days, or from about 7to about 10 days, or from about 7 to about 15 days, or longer. In someembodiments, the methods comprise chronic administration. In yet otherembodiments, the methods comprise administration over the course ofseveral weeks, months, years or decades. In still other embodiments, themethods comprise administration over the course of several weeks. Instill other embodiments, the methods comprise administration over thecourse of several months. In still other embodiments, the methodscomprise administration over the course of several years. In still otherembodiments, the methods comprise administration over the course ofseveral decades.

The dosage administered can vary depending upon known factors such asthe pharmacodynamic characteristics of the active ingredient and itsmode and route of administration; time of administration of activeingredient; age, sex, health and weight of the recipient; nature andextent of symptoms; kind of concurrent treatment, frequency of treatmentand the effect desired; and rate of excretion. These are all readilydetermined and may be used by the skilled artisan to adjust or titratedosages and/or dosing regimens.

The precise dose to be employed in the compositions will also depend onthe route of administration, and should be decided according to thejudgment of the practitioner and each subject's circumstances. Inspecific embodiments of the disclosure, suitable dose ranges for oraladministration of the compounds of the disclosure are generally about 1mg/day to about 1000 mg/day. In some embodiments, the oral dose is about1 mg/day to about 800 mg/day. In some embodiments, the oral dose isabout 1 mg/day to about 500 mg/day. In some embodiments, the oral doseis about 1 mg/day to about 250 mg/day. In some embodiments, the oraldose is about 1 mg/day to about 100 mg/day. In some embodiments, theoral dose is about 5 mg/day to about 50 mg/day. In some embodiments, theoral dose is about 5 mg/day. In some embodiments, the oral dose is about10 mg/day. In some embodiments, the oral dose is about 20 mg/day. Insome embodiments, the oral dose is about 30 mg/day. In some embodiments,the oral dose is about 40 mg/day. In some embodiments, the oral dose isabout 50 mg/day. In some embodiments, the oral dose is about 60 mg/day.In some embodiments, the oral dose is about 70 mg/day. In someembodiments, the oral dose is about 100 mg/day. It will be recognizedthat any of the dosages listed herein may constitute an upper or lowerdosage range, and may be combined with any other dosage to constitute adosage range comprising an upper and lower limit.

Any of the compounds and/or compositions of the disclosure may beprovided in a kit comprising the compounds and/or compositions. Thus, insome embodiments, the compound and/or composition of the disclosure isprovided in a kit.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the disclosure described herein. Such equivalents areintended to be within the scope of the present disclosure.

The disclosure is further described by the following non-limitingExamples.

Examples

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein arecontemplated as compounds of the disclosure.

Examples are provided herein to facilitate a more complete understandingof the disclosure. The following examples serve to illustrate theexemplary modes of making and practicing the subject matter of thedisclosure. However, the scope of the disclosure is not to be construedas limited to specific embodiments disclosed in these examples, whichare illustrative only. The compounds of Formula (I), for example, cangenerally be prepared according to exemplary Scheme 1:

where X, R¹, R⁶, R⁴, U, V, B and D are as defined as elsewhere herein, Qis independently a halogen, such as Cl, Br, I, and the like, or anyother leaving group, such as OSO₂Me, OMs, OTs, OTf, and the like. LG isa leaving group, such as Cl, Br, I, OTs, OTf, and the like, and P is aprotecting group, such as 4-methoxybenzyl and the like. Alternativeprotecting groups that can be used are described, e.g., in Greene etal., Protective Groups in Organic Synthesis (4^(th) ed. 2006).

As shown in Scheme 1, an aryl compound such as a compound of Formula1001 undergoes a cross-coupling reaction with a metalated or otherwiseactivated moiety to provide a compound of Formula 1002. The compound ofFormula 1002 then undergoes a substitution reaction with an amine suchas Compound 1005, followed by removal of the protecting group to providea compound of Formula (I). In some embodiments, LG is I. In someembodiments, LG is Cl. In some embodiments, LG is OTf or OTs.Alternatively, a protected heteroaryl ether, such as a compound ofFormula 1003, undergoes a cross-coupling reaction to provide a compoundof Formula 1004. The ether protecting group is subsequently removed andthe resulting hydroxyl group activated to form a Q group, such asOSO₂Me, OMs, OTs, OTf, and the like, to form a compound of Formula 1002,which can then be carried forward to prepare compounds having theFormula (I).

Alternatively, compounds of the disclosure can generally be preparedaccording to exemplary Scheme 2:

wherein X, R¹, R⁶, R⁴, U, V, B and D are as defined as elsewhere herein,Q is independently a halogen, such as Cl, Br, I, and the like, or anyother leaving group, such as OSO₂Me, OMs, OTs, OTf, and the like. LG isa leaving group, such as Cl, Br, I, OTs, OTf, and the like, and P is aprotecting group, such as 4-methoxybenzyl and the like. Alternativeprotecting groups that can be used are described, e.g., in Greene etal., Protective Groups in Organic Synthesis (4^(th) ed. 2006).

As shown in Scheme 2, an aryl compound such as a compound of Formula1001 undergoes a undergoes a substitution reaction with an amine such as1005 to provide a compound of Formula 1006. The compound of Formula 1006then undergoes a cross-coupling reaction with a metalated or otherwiseactivated moiety to provide a compound of Formula 1007. In someembodiments, the compound of Formula 1007 can be deprotected to producea compound of Formula (I). In other embodiments, the compound of Formula1007 can be left protected and functional groups on the R¹ moietyrefunctionalized by methods known to those of ordinary skill in the art.

In some embodiments, the cross-coupling reaction is a Buchwald-Hartwigreaction. In some embodiments, the cross-coupling reaction is a Chan-Lamcoupling reaction. In some embodiments, the cross-coupling reaction isan Ullmann reaction. In some embodiments, the cross-coupling reaction isa Suzuki reaction. In some embodiments, the cross-coupling reaction is aStille reaction. In some embodiments, the cross-coupling reaction is aNegishi reaction. In some embodiments, the cross-coupling reaction is aHiyama reaction. Other cross-coupling reactions may be employed as wouldbe apparent to one of ordinary skill in the art.

In some embodiments, the protecting group is removed under acidicconditions, such as HBr in AcOH. Conditions for removal of theprotecting group will depend on the nature of the protecting group.Conditions for the removal of various protecting groups can be found,e.g., in Greene et al., Protective Groups in Organic Synthesis (4^(th)ed. 2006).

Reactions were monitored and final products were characterized using oneof the following methods. LCMS standard conditions were: Waters HPLCsystem equipped with an Alliance 2695 main module, Waters 996 diodearray detector and ZQ micromass ESI-MS detector. Mobile phase A: H₂O(10.0 mM NH₄HCO₂), mobile phase B: CH₃CN. HPLC conditions were: XBridgeC18 column, 4.6×30 mm, 3.5 m, 0.0-0.2 min. isocratic (5% B), 0.2-2.0min. gradient (5-100% B), 3.0-3.0 min. isocratic (100% B); flow rate:3.0 mL/min; UV channel: 254 nm.

Purification of some racemic products was performed using semipreparative HPLC A, semi preparative HPLC B, or semi preparative SFC.Semi preparative HPLC A: Gilson 215 system equipped with a Waters 996diode array detector and a Waters 2525 pump. Semi preparative HPLC B:Waters 2767 system equipped with a Waters 996 diode array detector, 2×Waters 515 pumps, a Waters 2525 pump and a ZQ micromass ESI-MS detector.Semi preparative SFC: Mettler Toledo Minigram SFC equipped with a KnauerK-2501 UV detector and an Alcott Model 1719 Autosampler.

Product homogeneity and enantiomeric excess determination were performedusing Analytical HPLC A: Agilent 1100 HPLC system equipped with anAgilent G1315A diode array detector.

Abbreviations

-   Ac: acetyl-   AcOH or HOAc: acetic acid-   ACN or MeCN: acetonitrile-   Anhyd: anhydrous-   Aq: aqueous-   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   Bn: benzyl-   Boc: tert-butoxycarbonyl-   Boc₂O: di-tert-butyl dicarbonate-   BPO: benzoyl peroxide-   BOP: (benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   CSA: camphorsulfonic acid-   d: days-   DAST: diethylaminosulfur trifluoride-   dba: dibenzylideneacetone-   DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene-   DCE: 1,2-dichloroethane-   DCM: dichloromethane-   DEA: diethylamine-   DHP: dihydropyran-   DIBAL-H: diisobutylaluminum hydride-   DIPEA: N,N-diisopropylethylamine-   DMA: N,N-dimethylacetamide-   DME: 1,2-dimethoxyethane-   DMAP: 4-dimethylaminopyridine-   DMF: N,N-dimethylformamide-   DMSO-dimethyl sulfoxide-   dppf: 1,1′-bis(diphenylphosphino)ferrocene-   EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   ee: enantiomeric excess-   ESI: electrospray ionization-   EA: ethyl acetate-   EtOAc: ethyl acetate-   EtOH: ethanol-   FA: formic acid-   h or hrs: hours-   HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium    hexafluorophosphate-   HCl: hydrochloric acid-   HPLC: high performance liquid chromatography-   IPA: isopropyl alcohol-   K₂CO₃: potassium carbonate-   LAH: lithium aluminum hydride-   LDA: lithium diisopropylamide-   M: molar-   MeOH: methanol-   Me₂S: dimethyl sulfide-   MeONa: sodium methylate-   Mel: iodomethane-   min: minutes-   mL: milliliters-   mM: millimolar-   mmol: millimoles-   MTBE: methyl tert-butyl ether-   nBuLi: n-butyllithium-   NaOH: sodium hydroxide-   Na₂SO₄: sodium sulfate-   NBS: N-bromosuccinimide-   NCS: N-chlorosuccinimide-   NMP: N-methylpyrrolidine-   NMR: Nuclear Magnetic Resonance-   ° C.: degrees Celsius-   PE: petroleum ether-   POCl₃: phosphorus oxychloride-   PPh₃: triphenylphosphine-   Rel: relative-   R.T. or rt: room temperature-   RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl-   sat: saturated-   SFC: supercritical fluid chromatography-   SOCl₂: sulfur dichloride-   TBAB: tetrabutylammonium bromide-   TEA: triethylamine-   Tf: trifluoromethanesulfonate-   TfAA, TFMSA or Tf₂O: trifluoromethanesulfonic anhydride-   TFA: trifluoracetic acid-   TIPS: triisopropylsilyl-   THF: tetrahydrofuran-   THP: tetrahydropyran-   TLC: thin layer chromatography-   wt: weight-   Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Syntheses of Intermediates6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine, Intermediate A

Step a:

In a 100 mL round-bottomed flask, 3,5-dichloropyrazine-2-carboxylic acid(3.65 g, 18.9 mmol) and NaHCO₃ (4.70 g, 22.7 mmol) were dissolved indimethylformamide (38 mL). Iodomethane (7.14 mL, 113 mmol) was addeddropwise and the resulting mixture stirred overnight at rt. The mixturewas diluted with water (50 mL) and extracted with ethyl acetate (3×15mL). The combined organics were washed with brine (4×10 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure.Methyl 3,5-dichloropyrazine-2-carboxylate (3.77 g, 96%) was obtained asa yellowish solid after drying under high vacuum for 2-3 h. ¹H-NMR (500MHz, CDCl₃) δ 8.57 (s, 1H), 4.03 (s, 3H).

Step b:

Methyl 3,5-dichloropyrazine-2-carboxylate (5.0 g, 24.2 mmol) wasdissolved in a 9:1 mixture of dry tetrahydrofuran (242 mL) and methanol(27 mL). The mixture was cooled to 1.5-2° C. with an ice/water bath andstirred at this temperature for 10 min. A 2 M solution of lithiumborohydride in THE (13.3 mL, 26.6 mmol) was then added carefully keepingthe temperature below 4-5° C. After addition, the reaction mixture wasstirred for an additional 10-15 min at 0-4° C. Methanol (120 mL) wasadded to the flask and the mixture stirred for 15 min at rt. Thereaction was slowly poured into a mixture of 1 M HCl solution (100 mL)and ethyl acetate (200 mL). The resulting mixture was stirred at rt for15 min. The aqueous layer was extracted with ethyl acetate (3×150 mL)and the combined organics washed with brine (2×100 mL), dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure.(3,5-Dichloropyrazin-2-yl)methanol (4.3 g, 99% yield) was obtained as ayellow oil after drying under high vacuum for 2 h. ¹H-NMR (500 MHz,CDCl₃) δ 8.52 (s, 1H), 4.85 (s, 2H).

Step c:

(3,5-Dichloropyrazin-2-yl)methanol (4.3 g, 24 mmol) was dissolved indichloromethane (100 mL) and MnO₂ (20.2 g, 240 mmol) was then added inone portion. The resulting dark heterogeneous mixture was stirred for 16h at rt. After this time, the reaction mixture was sonicated for 5 min.and additional MnO₂ (4 g) was added to the reaction mixture. Theresulting suspension was stirred for 2 h at rt. Then the mixture wasfiltered over a pad of celite, and the cake washed with dichloromethane.The filtrate was concentrated under reduced pressure, affording3,5-dichloropyrazine-2-carbaldehyde (2.36 g, 56% yield) as pale yellowoil after drying under high vacuum for 30 min. ¹H-NMR (500 MHz, CDCl₃) δ10.29 (s, 1H), 8.71 (s, 1H).

Step d:

3,5-Dichloropyrazine-2-carbaldehyde (2.9 g, 16.4 mmol) was dissolved inN-methyl-2-pyrrolidone (16 mL), then hydrazine hydrate (0.78 mL, 49.2mmol) was added dropwise. The resulting brown suspension was stirred at65° C. for 40 min. After this time, additional hydrazine hydrate (0.4mL) was added and the mixture stirred at 65° C. for 2 h. The mixture wascooled to rt, poured into 1 M HCl solution (100 mL), and ethyl acetate(400 mL) was added. The aqueous layer was extracted with ethyl acetate(2×100 mL) and the combined organics washed with brine (300 mL), driedover anhydrous MgSO₄, filtered, and concentrated under reduced pressure.The yellow crude residue was purified by reversed phase chromatography(0 to 50% gradient of acetonitrile/10 mM aqueous ammonium formate)affording 6-chloro-1H-pyrazolo[3,4-b]pyrazine (800 mg, 32% yield) as alight brown solid after lyophilization. ¹H-NMR (500 MHz, CD₃OD) δ 8.58(s, 1H), 8.34 (s, 1H).

Step e:

6-Chloro-1H-pyrazolo[3,4-b]pyrazine was dissolved in acetonitrile (24mL). N-iodosuccinimide (3.43 g, 14.5 mmol) and tetrafluoroboric acidsolution (2.8 mL, 21.7 mmol, 48% in water) were successively added. Theresulting brown/orange mixture was then stirred at reflux for 2 h. Abeige/brown precipitate formed and the mixture cooled to roomtemperature, then placed into an ice/water bath for 5 min. The resultingsolid was collected by filtration and washed with cold acetonitrile togive 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (1.81 g, 89% yield) as ayellow solid after drying under high vacuum. LCMS [M+H]⁺=280.9; ¹H-NMR(500 MHz, CDCl₃) δ 8.59 (s, 1H).

Step f:

6-Chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (850 mg, 3 mmol) wasdissolved in dichloromethane (15 mL). 3,4-Dihydro-2H-pyran (0.85 mL, 9.1mmol) and p-toluenesulfonic acid monohydrate (176 mg, 0.91 mmol) weresuccessively added to the flask. The resulting mixture was stirred atroom temperature for 10 min. The mixture became homogeneous and darkishovertime. After this time, a saturated aqueous solution of NaHCO₃ (20mL) was added to the flask and the biphasic mixture stirred for 10 min.The layers were separated, and organic layer washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The crude residue was purified by flash chromatography (0 to50% gradient of ethyl acetate/hexanes) to give6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine(1.02 g, 93% yield) as an off-white solid after drying under high vacuumovernight. LCMS [M+H]⁺=364.9, [M-THP+H]⁺=281.0; ¹H NMR (500 MHz, CDCl₃)δ 8.56 (s, 1H), 5.96 (dd, J=10.4, 2.6 Hz, 1H), 4.16-4.06 (m, 1H),3.82-3.74 (m, 1H), 2.72-2.58 (m, 1H), 2.21-2.11 (m, 1H), 2.01-1.94 (m,1H), 1.89-1.70 (m, 2H), 1.69-1.59 (m, 1H).

Methyl 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate,Intermediate B

Step a:

A solution of sodium hydride (213 mg, 5.34 mmol) in DMF (10 mL) wascooled to 0° C., then 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (1 g,3.56 mmol, synthesized via Steps a-e of Intermediate B) was added. Thereaction mixture was allowed to warm to rt and the reaction was stirredfor 2.25 hr. The reaction mixture was then cooled to 0-10° C. and methylcarbonochloridate (817 μL, 10.6 mmol) was added and the reaction mixturewas stirred for 20 min. On completion, water was added (20 mL), then themixture was poured in water (60 mL). The reaction mixture was filtered,and the solid washed with water to give methyl6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate as a whitesolid (1.71 g, crude). LCMS m/z [M+H]⁺=338.9.

[6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methylacetate, Intermediate C

Step a:

A round bottomed flask was charged with methyl6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate (525 mg, 1.55mmol, Intermediate B), 2-(acetyloxy)acetic acid (1.46 g, 12.4 mmol),silver nitrate (52.6 mg, 0.31 mmol), and acetonitrile (15 mL) and water(9 mL). To the mixture was added ammonium persulfate (2.82 g, 12.4mmol), and the reaction was heated to 85° C. After 2 h, the reaction wascooled to room temperature and poured into ethyl acetate and brine. Theorganic layer was pre-absorbed onto silica gel and purified by columnchromatography (eluting with ethyl acetate and heptanes) to affordmethyl5-[(acetyloxy)methyl]-6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate(225 mg, 35% yield) as a white solid. LCMS m/z [M+H]⁺=410.9.

Step b:

A reaction tube containing methyl5-[(acetyloxy)methyl]-6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate(220 mg, 0.5358 mmol) in dichloromethane (4 mL) was charged withpiperidine (52.9 μL, 0.5358 mmol) at room temperature. After 15 min,further piperidine (0.2 equiv) was added. After 15 min,3,4-dihydro-2H-pyran (145 μL, 1.60 mmol) and 4-methylbenzene-1-sulfonicacid (92.2 mg, 0.5358 mmol) were added. After 30 min, the reactionmixture was pre-absorbed onto silica gel and purified by columnchromatography (eluting with ethyl acetate and heptanes) to afford[6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methylacetate as a white solid. LCMS m/z [M+H]⁺=437.0.

tert-butyl3-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate,Intermediate D

To a solution of NaH (486 mg, 60%) in DMF (20 mL) was added2,3-dihydro-1H-inden-1-one (541 mg, 4.10 mmol) in DMF (10 mL). Thereaction was stirred at 10° C. for 30 min. Then tert-butylN-(2-chloroethyl)-N-(2-iodoethyl)carbamate (1.37 g, 4.10 mmol) in DMF(10 mL) was added and the reaction was stirred and heated to 50° C. for12 hours. The reaction mixture was diluted with water (100.0 mL) andextracted ethyl acetate (100.0 mL×2). The combined organic layers werewashed with water (100.0 mL) and brine (100.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (petroleumether/ethyl acetate=100:0 to 100:10) to give tert-butyl3-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (220 mg,18% yield) as a brown oil. LCMS m/z [M+H−100]⁺=202.1.

1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine, Intermediate E

In a microwave vial was added tert-butyl5-chloro-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(500 mg, 1.65 mmol, Intermediate D) and MeOH (2.5 mL). Then acetic acidamine (1.90 g, 24.7 mmol) and sodium iminomethanide triboran-1-yliumtrihydride (175 mg, 1.98 mmol) were added to the reaction mixture, whichwas heated at 110° C. under microwave for 1 h. Then, another 15 eq. ofammonium acetate and 1.2 eq. of sodium cyanoborohydride were added andthe reaction mixture was heated under microwave at 110° C. for 1.5 h.The reaction mixture was then concentrated and then 2N NaOH (5 mL) wasadded. The mixture was then extracted with EtOAc (2×5 mL) and theorganic layer was dried over Na₂SO₄. The mixture was filtered andconcentrated give the crude product as a colorless oil. The oil waspurified by column chromatography (0-10% MeOH in DCM w/1% NH4OH) to givetert-butyl 3-amino-1,3-dihydrospiro[indene-2,4 (185 mg, 0.612 mmol).This intermediate was then dissolved in DCM (4 mL) and TFA (1 mL) wasadded and the reaction mixture was stirred at rt for 16 h. The reactionmixture was concentrated in vacuo, and the residue was azeotroped 3×with toluene. 1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine (307 mg,43% yield, 2 TFA salt) was isolated as a foamy solid. LCMS m/z[M+H]⁺=203.1.

tert-butyl(1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate F

Step a:

A mixture of 1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminedihydrochloride (800.0 mg, 2.9 mmol, Intermediate E),6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (1.05 g, 2.9mmol, Intermediate A) and Et₃N (2.0 mL, 14.4 mmol) in DMF (20 mL) wasstirred at 60° C. for 1 hour. To the reaction mixture was added Boc₂O(757.0 mg, 3.5 mmol) and the reaction was stirred at 60° C. for another2 hours. The reaction mixture was diluted with EtOAc (150 mL), andwashed with water (100 mL×3). The organic layer was concentrated andpurified by silica gel column (EtOAc in petroleum ether=0˜20%) to givetert-butylN-{1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(1.50 g, 82% yield) as a white solid. LCMS m/z [M+H]⁺=653.1.

(6-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate, Intermediate G

Step a:

To a vial with[6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methylacetate (76 mg, 0.1740 mmol, Intermediate C) in DMF (0.13 mL, 1 mL) wasadded 1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine ditrifluoroacetate(89.4 mg, 0.2088 mmol, Intermediate E) in 1 mL DMF andethylbis(propan-2-yl)amine (121 μL, 0.696 mmol, Hunig's base). The vialwas sealed and the mixture heated to 75° C. After 1 hr, moredihydrospiro[indene-2,4′-piperidin]-3-amine ditrifluoroacetate was addedwith Hunig's base (240 uL). Upon formation of(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate, tert-butyl dicarbonate (56.9 mg, 0.261 mmol) was added and thereaction mixture was stirred at rt for 48 h. To complete the conversion,another 35 mg of Boc₂O was added and the reaction mixture was heated to75° C. for 20 min. The reaction mixture was cooled to rt, then 5% w/wLiCl solution was added and the mixture was extracted with EtOAc. Theorganic layer was concentrated in vacuo and the residue was purified bycolumn chromatography (10 g column, 10-50% EtOAc in hexanes) to give(6-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate (85 mg, 71% yield). LCMS m/z [M+H]⁺=703.3.

tert-butyl(S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate,Intermediate H

Step a:

Dissolved tert-butyl3-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (1 g, 3.31mmol, Intermediate D) in 2-Me-THF (20 mL). Then tetratitanium-1-yliumtetraethanolate (4.50 mL, 13.2 mmol) was added followed by(R)-2-methylpropane-2-sulfinamide (721 mg, 5.95 mmol) and the reactionmixture was stirred at 90° C. for 16 h. The reaction mixture was thencooled to 0° C. and lithium(1+) borohydride (79.2 mg, 3.64 mmol) wasadded portion-wise and the mixture was stirred for 0.5 h. The reactionwas then quenched with methanol and concentrated in vacuo. EtOAc andwater were added and the mixture was extracted with EtOAc, and theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (24 g column, 0-100% EtOAcin heptanes) to give tert-butyl(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(500 mg, 21% yield) as a white solid. LCMS m/z [M+H−100]⁺=307.0.

(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine, Intermediate I

Step a:

Dissolved tert-butyl(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(500 mg, 1.22 mmol, Intermediate H) in MeOH (15 mL) and added hydrogenchloride (3.05 mL, 12.2 mmol), and the reaction mixture was stirred atrt for 16 h. Then 1 mL more 4N HCl was added and the reaction mixturewas stirred at rt for 1 h, then heated to 60° C. for 2 h. The reactionmixture was then concentrated. MBTE was added to the residue which wasthen filtered to give(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (335 mg, 99% yield)as a white solid. LCMS m/z [M+H]⁺=203.1.

tert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate J

Step a:

Dissolved (3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminedihydrochloride (1.37 g, 5.01 mmol, Intermediate I) in DMF (15 mL), thenadded6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine(2 g, 7.13 mmol, Intermediate A) followed by ethylbis(propan-2-yl)amine(4.97 mL, 28.5 mmol). The reaction was stirred at 75° C. for 3 h to form(1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine.The reaction mixture was cooled to rt then divided in half. To ˜10 mLreaction mixture was added di-tert-butyl dicarbonate (1.79 mL, 7.84mmol) and the reaction mixture was stirred at rt for 16 h. To thereaction mixture was added EtOAc and water, and the reaction wasextracted with EtOAc 3 times. The combined organic layer was dried overMgSO₄, filtered and concentrated onto silica gel. The mixture waspurified by column chromatography (0-45% EtOAc in heptanes) to givetert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(955 mg, 1.51 mmol). LCMS m/z [M+H]⁺=631.1.

(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate, Intermediate K

Step a:

Dissolved[6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methylacetate (528 mg, 1.21 mmol, Intermediate C) in DMF (10 mL). Then added(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(335 mg, 1.21 mmol, Intermediate I) followed byethylbis(propan-2-yl)amine (844 μL, 4.84 mmol) to the reaction and themixture was stirred at 75° C. for 16 h. The reaction mixture was thencooled to rt and di-tert-butyl dicarbonate (305 μL, 1.33 mmol) was addedand the reaction was stirred at rt for 3 h. The reaction was thendiluted with EtOAc and water. The layers were separated, then theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated directly onto SiO₂. The mixture was purified by columnchromatography (0-50% EtOAc in heptanes) to give(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate (500 mg, 54% yield) as an off-white solid. LCMS m/z[M+H]⁺=703.3.

1-(1,2,3,4-tetrahydroquinoxalin-1-yl)ethan-1-one, Intermediate L

Step a:

To a solution of 1,2,3,4-tetrahydroquinoxaline (500.0 mg, 3.7 mmol, CAS#3476-89-9) and Et₃N (770.0 uL, 5.6 mmol) in DCM (20 mL) at 0° C. wasadded AcCl (289.0 uL, 4.1 mmol) in DCM (5 mL) and the reaction wasstirred at 0° C. for 0.5 hour. The reaction was concentrated andpurified by silica gel column (EtOAc in Petroleum ether=50%) to give1-(1,2,3,4-tetrahydroquinoxalin-1-yl)ethan-1-one (530.0 mg, 80.9% yield)as a yellow solid. LCMS m/z [M+H]⁺=177.1.

1-(Oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl4-methylbenzene-1-sulfonate, Intermediate M

Step a:

A solution of BnOH (30.8 g, 0.285 mol, 29.6 mL, 1.1 eq) in THE (450 mL)was cooled to 0° C. NaH (12.4 g, 0.311 mol, 60% oil dispersion, 1.2 eq)was added slowly to the mixture at 0° C. After addition, the mixture wasstirred at 25° C. for 1 hr. The resultant solution was added a solutionof 3,5-dichloropyrazine-2-carbonitrile (45.0 g, 258.64 mmol, 1.0 eq) inTHE (450 mL) at −78° C. and the mixture was stirred at −78° C. for 0.5hr. The reaction was then poured into water (1.00 L) and extracted withEtOAc (1.00 L*3). The combined organic layer was washed with brine (500mL), dried over Na₂SO₄, filtered and concentrated. The residue wasslurryed in petroleum ether/EtOAc=10:1 (1.50 L) at 25° C. for 0.5 hr.The mixture was filtered and the filter cake was washed with petroleumether (200 mL). The filter cake was dried under reduced pressure to give5-(benzyloxy)-3-chloropyrazine-2-carbonitrile (79.3 g, 300 mmol, 58%yield, 93% purity) as a white solid. LCMS m/z [M+H]⁺=245.9. ¹H NMR (400MHz CDCl₃) δ 8.23 (s, 1H), 7.51-7.39 (m, 5H), 5.48 (s, 2H).

Step b:

To a solution of 5-(benzyloxy)-3-chloropyrazine-2-carbonitrile (20.0 g,75.6 mmol, 1.0 eq) in THE (200 mL) was added DIBAL-H (1.0 M, 227 mL, 3.0eq) at −78° C. under N₂. The mixture was stirred at −78° C. for 1 hr.The reaction was quenched by a solution of 10% aqueous HOAc (2.00 L) at−78° C. and extracted with EtOAc (1.50 L*3). The combined organic layerwas adjusted pH to 8-9 with saturated aqueous of NaHCO₃ and separated.The organic layer was washed with brine (1.00 L), dried over Na₂SO₄,filtered and concentrated. The residue was slurryed in mix solution ofEtOAc (300 mL) and petroleum ether (6.00 L). The precipitate wascollected by filtration to give5-(benzyloxy)-3-chloropyrazine-2-carbaldehyde (11.3 g) as a brown oil.LCMS m/z [2M+H]⁺=497.9; ¹H NMR (400 MHz CDCl₃) δ 10.27 (s, 1H), 8.33 (s,1H), 7.50-7.40 (m, 5H), 5.51 (s, 2H).

Step c:

To a mixture of 5-(benzyloxy)-3-chloropyrazine-2-carbaldehyde (11.3 g,45.4 mmol, 1.0 eq) and NH₂NH₂.H₂O (6.96 g, 137 mmol, 6.76 mL, 3.0 eq) inEtOH (113 mL) was stirred at 25° C. Then Et₃N (23.0 g, 228 mmol, 31.6mL, 5.00 eq) was added to the mixture at 25° C. The mixture was heatedto 80° C. and stirred at 80° C. for 16 hrs. Then the reaction wasconcentrated to give a residue. The residue was dissolved with EtOAc(500 mL) and washed with sat.aq.NH₄Cl (500 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated to give6-(benzyloxy)-1H-pyrazolo[3,4-b]pyrazine (9.5 g, 84% purity, 47% yieldover Step b-c) as a brown solid. LCMS m/z [M+H]⁺=227.0; ¹H NMR (400 MHzCDCl₃) δ 11.07 (br s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.50-7.47 (m,2H), 7.44-7.36 (m, 3H), 5.46 (s, 2H).

Step d:

To a solution of 6-(benzyloxy)-1H-pyrazolo[3,4-b]pyrazine (9.50 g, 35.4mmol, 1.0 eq) in DMF (190 mL) was added NIS (10.4 g, 46.0 mmol, 1.3 eq)at 25° C. Then the mixture was heated to 80° C. and stirred for 1 h. Thereaction was then cooled to 25° C. and then poured into ice-water (2.00L). The mixture was extracted with EtOAc (2.00 L). The organic layer waswashed with 10% aq.Na₂SO₃ (500 mL*2) and brine (500 mL), dried overNa₂SO₄, filtered and concentrated to give6-(benzyloxy)-3-iodo-1H-pyrazolo[3,4-b]pyrazine (24.7 g, 97% yield) as ayellow solid. LCMS m/z [M+H]⁺=352.8; ¹H NMR (400 MHz CDCl₃) δ 10.73 (brs, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.50-7.47 (m, 2H), 7.44-7.38 (m,3H), 5.46 (s, 2H).

Step e:

To a solution of 6-(benzyloxy)-3-iodo-1H-pyrazolo[3,4-b]pyrazine (12.1g, 34.3 mmol, 1.0 eq) in DCM (20.0 mL) was added DHP (8.65 g, 103 mmol,9.40 mL, 3.0 eq) and TsOH.H₂O (1.96 g, 10.3 mmol, 0.3 eq). The mixturewas stirred at 25° C. for 0.5 hr. Three batched in parallel werecombined for work-up. The mixture was poured into saturated NaHCO₃solution (250 mL) and then extracted with EtOAc (250 mL*2). The organiclayers were combined and washed with brine (500 mL), dried over Na₂SO₄,filtered and then concentrated under vacuum. The residue was purified bysilica gel chromatography (petroleum ether:EtOAc=30:1) to give6-(benzyloxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine(34.0 g, 72% yield) as a yellow solid. LCMS m/z [M+H]⁺=436.8; ¹H NMR(400 MHz CDCl₃) δ 8.24 (s, 1H), 7.51 (br d, J=6.8 Hz, 2H), 7.45-7.37 (m,3H), 5.87 (dd, J=2.6, 10.2 Hz, 1H), 5.50 (d, J=1.6 Hz, 2H), 4.19-4.11(m, 1H), 3.84-3.75 (m, 1H), 2.74-2.61 (m, 1H), 2.23-2.14 (m, 1H), 1.99(br dd, J=2.4, 12.8 Hz, 1H), 1.86-1.75 (m, 2H), 1.69-1.63 (m, 1H).

Step f:

To a mixture of6-(benzyloxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine(12.9 g, 27.9 mmol, 1.00 eq) and 1,2,3,4-tetrahydro-1,5-naphthyridine(3.74 g, 27.9 mmol, 1.00 eq) in toluene (130 mL) was added RuPhos (2.60g, 5.57 mmol, 0.2 eq), Pd₂(dba)₃ (766 mg, 836 umol, 0.03 eq) and Cs₂CO₃(27.3 g, 83.6 mmol, 3.0 eq) at 25° C. under N₂. The mixture was heatedto 100° C. and stirred at 100° C. for 20 hrs. The mixture was filteredand to the filtrate was added water (500 mL) and extracted with EtOAc(500 mL). The combined organic layer was washed with 0.5 M aq.HCl (200mL). The aqueous layer was further extracted with DCM (200 mL*2). Thecombined organic layers (EtOAc and DCM) were washed with sat. NaHCO₃(200 mL), brine (200 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by flash silica gel chromatography (330 gsilica column, eluent of 10˜30% ethyl acetate/petroleum ether) to give1-(6-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine(17.6 g, 64% yield) as a yellow solid. LCMS m/z [M+H]⁺=443.1; ¹H NMR(400 MHz CDCl₃) δ 8.12 (s, 1H), 8.05 (dd, J=1.2, 4.6 Hz, 1H), 7.70 (dd,J=1.2, 8.4 Hz, 1H), 7.52 (br d, J=6.8 Hz, 2H), 7.45-7.35 (m, 3H), 6.97(dd, J=4.6, 8.4 Hz, 1H), 5.86 (dd, J=2.4, 10.2 Hz, 1H), 5.50 (d, J=2.2Hz, 2H), 4.19-4.12 (m, 2H), 3.86-3.76 (m, 1H), 3.07 (t, J=6.6 Hz, 2H),2.73-2.58 (m, 1H), 2.25-2.13 (m, 3H), 1.98 (br d, J=12.8 Hz, 1H), 1.80(br t, J=9.7 Hz, 2H), 1.74-1.63 (m, 2H).

Step g:

To a solution of1-(6-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine(9.00 g, 20.4 mmol, 1.00 eq) in MeOH (950 mL) was added Pd(OH)₂/C (1.14g, 4.07 mmol, 50% purity, 0.20 eq) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (50 psi) at 25° C. for 30 hrs. 2 batches in parallel werecombined for work-up. The mixture was filtered and the filter cake wasdried under reduced pressure to give3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-ol(13.7 g) which contained Pd(OH)₂/C as a blackish solid. ¹H NMR (400 MHzCDCl₃) δ 12.60 (br s, 1H), 8.05-7.91 (m, 2H), 7.64 (br d, J=8.4 Hz, 1H),7.02 (dd, J=4.4, 8.2 Hz, 1H), 5.68 (br d, J=8.7 Hz, 1H), 4.02 (br s,2H), 3.94 (br d, J=11.2 Hz, 1H), 3.67-3.58 (m, 1H), 2.94 (br t, J=6.4Hz, 2H), 2.40-2.30 (m, 1H), 2.11-1.98 (m, 3H), 1.89 (br d, J=10.8 Hz,1H), 1.71 (br s, 1H), 1.55 (br s, 2H).

Step h:

To a mixture of3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-ol(7.00 g, 19.9 mmol, 1.0 eq) in DCM (70.0 mL) was added DIPEA (2.82 g,21.9 mmol, 3.81 mL, 1.1 eq) at 25° C. Then the mixture was cooled to 0°C. and added a solution of p-TsCl (4.54 g, 23.9 mmol, 1.20 eq) in DCM(70.0 mL) at 0° C. The mixture was stirred at 0˜10° C. for 1 hr. 2batches in parallel were combined for work-up. The reaction was pouredinto ice-water (250 mL) and extracted with EtOAc (250 mL*3). Thecombined organic layer was washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (petroleum ether:EtOAc=5:1 to 1:1) to give3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl4-methylbenzenesulfonate (16.4 g, 76% yield) as a red foam. LCMS m/z[M+H]⁺=507.1; ¹H NMR (400 MHz CDCl₃) δ 8.23 (s, 1H), 8.10 (dd, J=1.4,4.6 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.76 (dd, J=1.4, 8.4 Hz, 1H), 7.41(d, J=8.2 Hz, 2H), 7.00 (dd, J=4.6, 8.4 Hz, 1H), 5.68 (dd, J=2.4, 10.5Hz, 1H), 4.19-4.13 (m, 2H), 4.10 (br s, 1H), 3.72 (dt, J=2.4, 11.2 Hz,1H), 3.06 (t, J=6.6 Hz, 2H), 2.59-2.51 (m, 1H), 2.49 (s, 3H), 2.22-2.11(m, 3H), 1.91 (br dd, J=2.2, 12.9 Hz, 1H), 1.79-1.71 (m, 2H), 1.64 (brd, J=6.8 Hz, 1H).

2,3-dihydrospiro[indene-1,4′-piperidin]-2-amine, Intermediate N

Step a:

Dissolved tert-butyl2-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (500 mg,1.65 mmol, CAS #241819-85-2) and 1-phenylmethanamine (264 mg, 2.47 mmol)in DCE (10 mL). Then acetic acid (9.42 μL, 0.165 mmol) was added and thereaction mixture was stirred at rt for 1 hr. Next, sodium cyanoboranuide(155 mg, 2.47 mmol) was added and the reaction was stirred at rt for 48h. The reaction was then heated to 50° C. for 2.5 h, then AcOH (90 uL)was added and the reaction was stirred at 50° C. for an additional 48 h.The reaction was then diluted with saturated aqueous sodium bicarbonatesolution (5 mL) and extracted with EtOAc (3×10 mL). The combined organicphases were washed with brine and concentrated. The residue was purifiedby column chromatography (0-100% EtOAc in heptanes) to give tert-butyl2-(benzylamino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(242 mg, 37% yield) as a yellow oil. LCMS m/z [M+H]⁺=393.5.

Step b:

Dissolved tert-butyl2-(benzylamino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(242 mg, 0.616 mmol) and trifluoroacetic acid (70.2 mg, 0.616 mmol) inMeOH (5 mL). The reaction mixture was then cycled through a H-Cube at 3bar hydrogen gas with a 10% Pd/C cartridge for 2 hr at rt. The reactionmixture was then concentrated and purified by column chromatography(0-100% EtOAc in heptanes, followed by 0-10% MeOH in DCM w/1% NH₄OH) togive tert-butyl2-amino-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (68 mg,37% yield).

Step c:

Dissolved tert-butyl2-amino-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (68 mg,0.23 mmol) in MeOH (2 mL), then added TFA (1 mL) and stirred thereaction mixture at rt for 1 h. The reaction mixture was concentrated,chased with toluene and dried under high vacuum for 1 h to give2,3-dihydrospiro[indene-1,4′-piperidin]-2-amine (40.0 mg, 41% yield,2TFA). LCMS m/z [M+H]⁺=203.3.

4-[cis-3-[(tert-butyldimethylsilyl)oxy]cyclobutyl]-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile,Intermediate O

Step a:

To a solution of cis-3-aminocyclobutan-1-ol hydrochloride (3.04 g, 24.6mmol) and Et₃N (10.3 mL, 73.8 mmol) in EtOH (100.0 mL) was added3-fluoro-4-nitrobenzonitrile (4.10 g, 24.6 mmol) at 40° C. The mixturewas stirred at 40° C. for 0.5 hour. The mixture was then concentrated invacuo to give crude product. The solid was triturated with EtOAc.Petroleum ether=1:4 and stirred for 20 min. The mixture was filtered andfiltrate cake was dried in vacuo to give3-[(3-hydroxycyclobutyl)amino]-4-nitrobenzonitrile (5.60 g, 98% yield)as an orange solid. LCMS m/z [M+H]⁺=234.0.

Step b:

A solution of 3-[(3-hydroxycyclobutyl)amino]-4-nitrobenzonitrile (5.60g, 24.0 mmol) and Pd/C (1.00 g, 10%) in MeOH (100.0 mL) was stirred at10° C. for 12 hours under H₂ (15 psi). The reaction mixture was thenfiltered and the filtrate was concentrated in vacuo to give4-amino-3-[(3-hydroxycyclobutyl)amino]benzonitrile (5.00 g, quant. crudeyield) as a yellow gum. LCMS m/z [M+H]⁺=203.9.

Step c:

A solution of 4-amino-3-[(3-hydroxycyclobutyl)amino]benzonitrile (5.00g, 24.6 mmol), 1,2-dibromoethane (18.40 g, 98.4 mmol), TBAB (31.70 g,98.4 mmol) and TEA (13.7 mL, 98.4 mmol) was stirred at 60° C. for 12hours. The solution was added into H₂O (500.0 mL) and then extractedwith EtOAc (500.0 mL×2). The combined organic layers were washed withbrine (500.0 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give crude product as orange gum. The residue was purifiedby flash silica gel chromatography (80 g column, ethyl acetate inpetroleum ether from 0% to 65%) to give4-[cis-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile(3.50 g, 62% yield) as an orange oil. LCMS m/z [M+H]⁺=230.1

Step d:

A solution ofcis-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile(3.50 g, 15.2 mmol), TBSCI (2.96 g, 19.7 mmol) and imidazole (2.06 g,30.4 mmol) in CH₂Cl₂ (30.0 mL) was stirred at 40° C. for 0.5 hour. Themixture was concentrated in vacuo. The residue was purified by flashsilica gel chromatography (40 g column, ethyl acetate in petroleum etherfrom 0% to 15%) to give4-[cis-3-[(tert-butyldimethylsilyl)oxy]cyclobutyl]-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile(2.50 g, 48% yield) as an orange oil. LCMS m/z [M+H]⁺=343.9. HPLC: 93.5%purity at 254 nm. ¹HNMR (400 MHz, CDCl₃): 6.83-6.86 (m, 1H), 6.57 (s,1H), 6.30-6.33 (m, 1H), 4.36 (s, 1H), 4.01-4.05 (m, 1H), 3.45-3.49 (m,2H), 3.17-3.23 (m, 1H), 3.01-3.06 (m, 2H), 2.65-2.70 (m, 2H), 1.89-1.95(m, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

4-(trans-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile,Intermediate P

4-(trans-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrilewas synthesized as described for Intermediate O, couplingtrans-3-aminocyclobutan-1-ol hydrochloride in Step a. Characterizationof the final intermediate: LCMS m/z [M+H]⁺=344.2. ¹HNMR (400 MHz,CDCl₃): 6.81-6.88 (m, 1H), 6.50-6.51 (m, 1H), 6.31-6.34 (m, 1H),4.29-4.36 (m, 1H), 3.90-3.97 (m, 1H), 3.49-3.50 (m, 2H), 3.01-3.04 (m,2H), 2.24-2.34 (m, 4H), 0.85 (s, 9H), 0.01 (s, 6H).

4-(trans-3-methoxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile,Intermediate Q

4-(trans-3-methoxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrilewas synthesized as described in Steps a-c of Intermediate O, couplingtrans-3-methoxycyclobutan-1-amine hydrochloride in Step a.Characterization of the final intermediate: LCMS m/z [M+H]⁺=243.9; ¹HNMR (400 MHz, CDCl₃): δ=7.02-6.95 (m, 2H), 6.64 (s, 1H), 6.42 (d, J=8.0Hz, 1H), 4.09-3.98 (m, 2H), 3.59 (t, J=5.0 Hz, 2H), 3.32 (s, 3H), 3.12(t, J=5.0 Hz, 2H), 2.46-2.32 (m, 4H).

4-(cis-3-methoxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile,Intermediate R

4-(cis-3-methoxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrilewas synthesized as described in Steps a-c of Intermediate 0, couplingcis-3-methoxycyclobutan-1-amine hydrochloride in Step a.Characterization of the final intermediate: LCMS m/z [M+H]⁺=244.1; ¹HNMR(400 MHz, CDCl₃): 6.94 (d, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.41 (d, J=8.0Hz, 1H), 4.37 (br, 1H), 3.70-3.78 (m, 1H), 3.56 (t, J=4.8 Hz, 2H),3.38-3.48 (m, 1H), 3.30 (s, 3H), 3.13 (t, J=4.8 Hz, 2H), 2.73-2.83 (m,2H), 1.93-2.03 (m, 2H).

6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine, Intermediate S

Step a:

The mixture of 3-bromo-6-chloropyrazin-2-amine (600 mg, 2.87 mmol, 1.0eq, CAS #212779-21-0), (2,3-dichlorophenyl)boronic acid (547 mg, 2.87mmol, 1.0 eq), Pd(dppf)Cl₂ (210 mg, 287 μmol, 0.1 eq) and K₃PO₄ (1.82 g,8.61 mmol, 3.0 eq) in dioxane (15 mL) and H₂O (3 mL) was evacuated andrefilled 3 times with N₂ gas, then stirred at 70° C. for 12 hours. Themixture was concentrated under reduced pressure to afford a residue,which was purified by column chromatography (petroleum ether/ethylacetate=1:0˜10:1) to afford6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine (630 mg, 80% yield) as ayellow solid. LCMS m/z [M+H]⁺=273.9/275.9.

(S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride, Intermediate T

Step a:

A round bottomed flask was charged with tert-butyl4-cyanopiperidine-1-carboxylate (533 mg, 2.53 mmol) and THE (10 mL)before being cooled to −78° C. for the addition oflithiobis(propan-2-yl)amine (2.90 mL, 2.90 mmol). After 45 min, asolution of 2-(bromomethyl)-1-fluoro-3-iodobenzene (954 mg, 3.03 mmol)in THE (2 mL) was added, and the reaction warmed to rt. After 45 min,the reaction was diluted with water and ethyl acetate. The organic layerwas pre-absorbed on silica gel (4 g) and was purified by columnchromatography (eluting with ethl acetate/heptanes) to yield tert-butyl4-cyano-4-[(2-fluoro-6-iodophenyl)methyl]piperidine-1-carboxylate (860mg, 76% yield) as a colorless oil. LCMS m/z [M+H]⁺=445.1.

Step b:

A round bottomed flask was charged with tert-butyl4-cyano-4-[(2-fluoro-6-iodophenyl)methyl]piperidine-1-carboxylate (860mg, 1.93 mmol), Pd/P(tBu)₃ G2 (98.8 mg, 0.1930 mmol), DMF (15 mL), water(1.5 mL), and triethylamine (320 μL, 2.31 mmol). Nitrogen was bubbledthrough the mixture for 5 min, before the vial was sealed and heated to130° C. After 3 h, additional Pd/P(tBu)₃ G2 (98.8 mg, 0.1930 mmol) andtriethylamine (233 mg, 2.31 mmol) was added, and the mixture was stirredat 130° C. overnight. The reaction was cooled to rt and partitionedbetween ethyl acetate, water, and brine. The organic layer waspre-absorbed on silica gel (4 g) and purified by column chromatography(eluting with ethyl acetate and heptanes) to afford tert-butyl4-fluoro-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(280 mg, 0.8767 mmol). LCMS m/z [M+H]⁺=320.7.

Step c:

A reaction tube was charged with tert-butyl4-fluoro-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(280 mg, 0.8767 mmol), (R)-2-methylpropane-2-sulfinamide (158 mg, 1.31mmol), 2-MeTHF, and tetratitanium-1-ylium tetraethanolate (1.19 mL, 3.50mmol). The vial was sealed and heated to 80° C. overnight. The mixturewas cooled to rt and charged with boranium lithiumuide (28.5 mg, 1.31mmol). After 2 h, the reaction was quenched with methanol andconcentrated in vacuo. The residue was taken up in ethyl acetate andwater. The aqueous layer was charged with celite, filtered andback-extracted with ethyl acetate. The combined organic fractions werepre-absorbed on silica gel (4 g), and purified by column chromatography(eluting with ethyl acetate and heptanes) to afford tert-butyl(3S)-7-fluoro-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1-carboxylate(175 mg, 0.412 mmol) as a colorless oil. LCMS m/z [M+H]⁺=425.2.

Step d:

A reaction tube was charged with tert-butyl(3S)-7-fluoro-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(170 mg, 0.40 mmol) and methanol (3 mL), followed by hydrogen chloride(1 mL, 4.00 mmol). The reaction mixture was stirred at rt for 16 h. Thesolvent was then removed in vacuo, and the residue was triturated withmethyl tertbutyl ether.(S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (150 mg) was isolated as a white solid followingfiltration and air drying to a constant weight. LCMS m/z [M+H]⁺=221.1.

tert-butyl((1S)-4-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate U

Step a:

Dissolved (3 S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminedihydrochloride (1.38 g, 4.70 mmol, Intermediate T) in DMF (12 mL).6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (1.71 g, 4.70mmol, Intermediate A) was then added followed byethylbis(propan-2-yl)amine (3.27 mL, 18.8 mmol) and the reaction mixturewas stirred at 75° C. for 2 h. The reaction mixture was then cooled tort and di-tert-butyl dicarbonate (1.17 mL, 5.17 mmol) was added and thereaction mixture was stirred at rt for 2 h. The reaction mixture wasthen diluted with EtOAc and water. The layers were separated, then theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated onto SiO₂. The mixture was purified via columnchromatography (0-100% EtOAc in heptanes) to give tert-butylN-[(3S)-7-fluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(392 mg, 13% yield). LCMS m/z [M+H]⁺=649.5.

(R)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride, Intermediate V

(R)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride was synthesized as described for Intermediate T, using(S)-2-methylpropane-2-sulfinamide in Step c to form tert-butyl(3R)-7-fluoro-3-{[(S)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate.(R)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride was isolated as a white solid. LCMS m/z [M+H]⁺=221.2.

6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine,Intermediate W

Step a:

To a solution of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (4.0 g,18.7 mmol) in dioxane (50 mL) and H₂O (5 mL) were added Cs₂CO₃ (12.1 g,37.4 mmol),1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.8 g, 28.0 mmol, CAS #903550-26-5) and Pd(dppf)Cl₂ (684 mg, 935 mmol).The mixture was stirred at 100° C. for 12 hours under N₂ atmosphere. Thereaction mixture was then concentrated in vacuo and purified by silicagel column (elution: petroleum ether:ethyl acetate=1:0 to 1:3) to give6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine(3.7 g, 70% yield) as a yellow solid. LCMS m/z [M+H]⁺=284.9. ¹HNMR (400MHz, CD₃OD): δ 7.55˜7.54 (m, 1H), 7.25 (d, J=6.4 Hz, 1H), 6.92 (d, J=6.4Hz, 1H), 6.48 (s, 1H), 5.94˜5.90 (m, 1H), 4.04˜4.00 (m, 1H), 3.61˜3.60(m, 1H), 3.34˜3.32 (m, 2H), 2.94˜2.92 (m, 2H), 2.48˜2.41 (m, 1H),2.12˜2.08 (m, 3H), 1.92˜1.90 (m, 1H), 1.78˜1.48 (m, 3H).

6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine,Intermediate X

Step a:

To the mixture of 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (2 g,11.8 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.93 g, 14.1 mmol) in dioxane (35.0 mL) and H₂O (5.0 mL) were addedPd(dppf)Cl₂ (1.29 g, 1.77 mmol) and K₃PO₄ (5.49 g, 25.9 mmol) under N₂.The mixture was stirred at 100° C. under N₂ for 3 hrs. The mixture wasthen concentrated in vacuo and purified by flash silica gelchromatography (petroleum ether/EtOAc=1/0 to 0/1) to give the product of6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (1.30g, 52% yield) as a brown solid. LCMS m/z [M]⁺=214.9.

(S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride, Intermediate Y

(S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine wassynthesized as described above for Intermediate T, using1-(bromomethyl)-4-fluoro-2-iodobenzene for the coupling in Step a. ¹HNMR (400 MHz, DMSO-d6) δ 8.80-9.04 (m, 2H), 8.65 (br s, 3H), 7.42 (dd,J=2.44, 9.03 Hz, 1H), 7.32 (dd, J=5.37, 8.30 Hz, 1H), 7.19 (dt, J=2.44,8.79 Hz, 1H), 4.41 (br d, J=4.64 Hz, 1H), 3.69-3.74 (m, 1H), 3.31 (br d,J=13.18 Hz, 1H), 2.89-3.20 (m, 5H), 1.94-2.10 (m, 1H), 1.68-1.84 (m,2H), 1.47-1.61 (m, 1H), 0.99-1.18 (m, 4H).

tert-butyl((3S)-5-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate,Intermediate Z

Step a:

6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (150 mg, 0.4114mmol, Intermediate A) in DMF (4 mL) was charged withethylbis(propan-2-yl)amine (355 μL, 2.05 mmol) and(S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (120 mg, 0.411 mmol, Intermediate Y) and the solutionwas heated to 75° C. for 4 hr. Then another 0.2 eq of6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (IntermediateA) was added and the reaction was stirred for 2 h at 75° C. The reactionwas then cooled to rt and di-tert-butyl dicarbonate (107 mg, 0.4936mmol) was added and the reaction was stirred at rt for 16 h. The mixturewas then partitioned between brine and EA. The org layer waspre-absorbed on SiO₂ (2 g) and purified on by column chromatography (12g column, 20-70% EA/hep) to give tert-butyl((3S)-5-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(175 mg, 66% yield) as a white solid. LCMS m/z [M+H]⁺=649.2.

1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine,Intermediate AA

Step a:

A vial was charged with6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (2 g, 5.48mmol, Intermediate A), XantPhos-Pd-G4 (263 mg, 0.274 mmol),1,2,3,4-tetrahydro-1,5-naphthyridine (720 mg, 5.37 mmol), and Cs₂CO₃(3.54 g, 10.9 mmol) in PhMe (20 mL). The mixture was bubbled withnitrogen for 10 min, then the vial was sealed and heated to 60° C. for48 h. The reaction mixture was cooled water and EA were added. Theorganic layer was washed with brine, dried, and concentrated. Theresidue was purified by column chromatography (Si-40 g column, 50-90%EA/hep) to afford1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine(1.48 g, 73% yield) as an orange solid. LCMS m/z [M+H]⁺=371.3.

Ethyl6-(2,3-dichlorophenyl)-5-methyl-3-(tosyloxy)pyrazine-2-carboxylate,Intermediate AB

Step a:

To the stirred mixture of propane-1,2-diamine (5.00 g, 67.4 mmol, 5.76mL, 1.00 eq) in EtOH (25.0 mL) was added diethyl 2-oxomalonate (11.7 g,67.4 mmol, 10.4 mL, 1.00 eq) dropwise at 0° C. The mixture was warmed to25° C. The reaction was stirred at 25° C. for 2 h, then the reaction wasstirred at 95° C. for 18 h. The reaction mixture was concentrated thenthe residue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=20:1˜0:1 then petroleum ethyl/ethylacetate/EtOH=8:3:1) to give ethyl3-hydroxy-5-methylpyrazine-2-carboxylate (2.24 g, 18% yield) as a yellowsolid. ¹H NMR (400 MHz DMSO-d₆) 12.8 (br s, 1H), 7.35 (br s, 1H), 4.25(q, J=7.2 Hz, 2H), 2.24 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).

Step b:

To the stirred solution of ethyl3-hydroxy-5-methylpyrazine-2-carboxylate (2.24 g, 12.3 mmol, 1.00 eq) inDMF (11.2 mL) was added NBS (2.30 g, 12.9 mmol, 1.05 eq) in one portionat 0° C. under N₂, then the mixture was stirred at 20° C. for 2 h. Thereaction mixture was poured into H₂O (60.0 mL) where solid precipitateformed. The suspension was filtered and the solid filtrate was driedunder reduced pressure to give ethyl6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate (1.90 g, 59% yield) asa light yellow solid. LCMS m/z [M+H]⁺=262.9; ¹H NMR (400 MHz DMSO-d₆)12.8 (br s, 1H), 4.30 (q, J=7.2 Hz, 2H), 2.45 (s, 3H), 1.29 (t, J=7.2Hz, 3H).

Step c:

To the stirred mixture of ethyl6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate (1.90 g, 7.28 mmol,1.00 eq) and K₂CO₃ (4.02 g, 29.1 mmol, 4 eq) in ACN (9.50 mL) and H₂O(1.90 mL) was added (2,3-dichlorophenyl)boronic acid (1.39 g, 7.28 mmol,1.00 eq) and Pd(dppf)Cl₂.CH₂Cl₂ (594 mg, 728 umol, 0.10 eq) under N₂ at20° C. The mixture was stirred at 90° C. for 1 h. To the mixture wasthen added H₂O (20.0 mL) and acidified with 0.5 N HCl to pH=7. Themixture was then extracted with ethyl acetate (40.0 mL×3). The combinedorganic layers were washed with brine (30.0 mL×2), dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash silica gelchromatography (petroleum ether/ethyl acetate=50/1˜1/1, R_(f)=0.6) togive ethyl6-(2,3-dichlorophenyl)-3-hydroxy-5-methylpyrazine-2-carboxylate (700 mg,29% yield) as a yellow solid. LCMS m/z [M+H]⁺=327.1; ¹H NMR (400 MHzCDCl₃) 11.47 (br s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H),7.27-7.25 (m, 1H), 4.56 (q, J=6.8 Hz, 2H), 2.42 (s, 3H), 1.45 (td, J=7.2Hz, 0.8 Hz, 3H).

Step d:

A solution ofethyl-6-(2,3-dichlorophenyl)-3-hydroxy-5-methylpyrazine-2-carboxylate(150.0 mg, 458.0 μmol), TsCl (130.0 mg, 686.0 umol) and DIPEA (241.0 uL,1.37 mmol) in CH₂Cl₂ (3.0 mL) was stirred at 20° C. for 1 hour. Thesolution was poured into H₂O (10.0 mL) and extracted with CH₂Cl₂ (10.0mL×2). The combined organic layers were washed with brine (20.0 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give ethyl6-(2,3-dichlorophenyl)-5-methyl-3-[(4-methylbenzenesulfonyl)oxy]pyrazine-2-carboxylate(240.0 mg, quant. crude yield) as an orange oil, which was used in thenext step without further purification. LCMS m/z [M+H]⁺=481.0/483.0.

Sodium 2-amino-3-chloropyridine-4-thiolate, Intermediate AC

Step a:

A 250 mL round bottomed flask was charged with3-chloro-4-iodopyridin-2-amine (1 g, 3.92 mmol),9-{[5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenyl-4-phosphanyl}-O-methanesulfonyl-8-methyl-8-4-aza-9-palladatricyclo[8.4.0.0²,7]tetradeca-1(14),2,4,6,10,12-hexaene-9,9-bis(ylium)-10-uid-9-olate(188 mg, 0.196 mmol), dioxane (30 mL), methyl 3-sulfanylpropanoate (476μL, 4.31 mmol) and ethylbis(propan-2-yl)amine (1.36 mL, 7.84 mmol). Themixture was bubbled with nitrogen for 5 min then the mixture was stirredat 100° C. for 1 h. The reaction mixture was diluted with EA, filteredthrough celite and washed with EA. The filtrate was pre-absorbed on SiO₂(8 g) and purified by column chromatography (40 g column, 0-50% EA/Hex)to give methyl 3-((2-amino-3-chloropyridin-4-yl)thio)propanoate (890 mg,92% yield). LCMS m/z [M]⁺=246.9.

Step b:

Methyl 3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]propanoate (890 mg,3.60 mmol), and ethoxysodium (1.40 mL, 3.78 mmol) were dissolved in THE(10 mL). The mixture was stirred at 25° C. for 10 min. The mixture wasdiluted with DCM (10-15 mL) and stirred until nucleation occurred; after5 min, large amount of solid formed in suspension. Additional DCM (86mL) was added, the reaction was filtered and the filter cake washed withDCM and was air dried. Sodium 2-amino-3-chloropyridine-4-thiolate (473mg, 71% yield) was isolated as a red/brown solid, which was stored inthe freezer until use. LCMS m/z [M+H−Na]⁺=160.9.

(S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate AD

(S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine wassynthesized as described above for Intermediate T, using2-(bromomethyl)-4-fluoro-1-iodobenzene for the coupling in Step a andusing (S)-2-methylpropane-2-sulfinamide in Step c. ¹H NMR (400 MHz,DMSO-d6) δ ppm 8.94 (br s, 2H) 8.58 (br s, 3H) 7.61 (br dd, J=7.81, 5.86Hz, 1H) 7.07-7.18 (m, 2H) 4.37 (br d, J=4.39 Hz, 1H) 3.71 (s, 1H) 3.31(br d, J=13.43 Hz, 1H) 3.13-3.22 (m, 2H) 2.87-3.10 (m, 3H) 1.95-2.11 (m,1H) 1.64-1.85 (m, 2H) 1.50 (br d, J=14.40 Hz, 1H) 1.09 (s, 4H).

6-(1,3-oxazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, IntermediateAE

Step a:

A mixture of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (1 g, 4.69mmol, CAS #1219022-46-4), 2-(tributylstannyl)-1,3-oxazole (2.51 g, 7.03mmol), Pd₂(dba)₃ (429 mg, 469 μmol) and XPhos (447 mg, 938 μmol) indioxane (30 mL) was stirred at 100° C. for 12 hours under N₂ atmosphere.After cooling to room temperature, KF (2 g) was added and the reactionmixture was stirred at 20° C. for 0.5 hour. The reaction mixture wasdiluted with ethyl acetate (60 mL), and washed with H₂O (30 mL×2). Theorganic phase was washed with brine (15 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (ethyl acetate aseluent) to afford6-(1,3-oxazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (260 mg, 28%yield) as a yellow oil. LCMS m/z [M]⁺=201.9.

4-(1-cyanocyclopropyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile,Intermediate AF

Step a:

To the mixture of 1-aminocyclopropane-1-carbonitrile hydrochloride (4.0g, 33.7 mmol) and TEA (13.9 mL, 101 mmol) in EtOH (60.0 mL) was added3-fluoro-4-nitrobenzonitrile (5.6 g, 33.7 mmol). The mixture was stirredat 90° C. for 12 hours. The mixture was concentrated in vacuo andpurified by flash silica gel chromatography (petroleum ether/EtOAc=1/0to 3/1) to give the product3-[(1-cyanocyclopropyl)amino]-4-nitrobenzonitrile (2.8 g, 36% yield) asa yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.34-8.24 (m, 2H), 7.64 (s,1H), 7.20-7.18 (m, 1H), 1.82-1.79 (m, 2H), 1.45-1.42 (m, 2H).

Step b:

To the mixture of 3-[(1-cyanocyclopropyl)amino]-4-nitrobenzonitrile (2.5g, 10.9 mmol) in MeOH (40.0 mL) was added 10% wet Pd/C (300.0 mg). Themixture was stirred at 15° C. under H₂ (15 psi) for 2 hours. The mixturewas filtered and the filtrate was concentrated in vacuo to give aresidue. The residue was purified by flash silica gel chromatography(petroleum ether/EtOAc=1/0 to 1/1) to give the product of4-amino-3-[(1-cyanocyclopropyl)amino]benzonitrile (1.1 g, 51% yield) asa brown solid. ¹HNMR (400 MHz, CDCl₃) δ 7.22-7.20 (m, 1H), 7.11-7.05 (m,1H), 6.68 (d, J=12.0 Hz, 1H), 4.29 (s, 1H), 3.70 (s, 2H), 1.58-1.51 (m,2H), 1.23-1.19 (m, 2H).

Step c:

A mixture of 4-amino-3-[(1-cyanocyclopropyl)amino]benzonitrile (500.0mg, 2.5 mmol), TBAB (3.2 g, 10.0 mmol), TEA (1.1 mL, 8.6 mmol) and1,2-dibromoethane (1.5 mL, 17.4 mmol) was stirred at 60° C. for 24hours. The mixture was poured into water (50 mL) and extracted with DCM(50 mL×3). The organic layers were washed with brine and dried overanhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo togive a residue. The residue was purified by flash silica gelchromatography (petroleum ether/EtOAc=1/0 to 1/1) to give the product of4-(1-cyanocyclopropyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile(175.0 mg, combined product) as an off-white solid. LCMS m/z[M+H]⁺=224.9; ¹H NMR (400 MHz, CDCl₃): δ=7.10 (s, 1H), 6.96 (d, J=8.0Hz, 1H), 6.38 (d, J=8.0 Hz, 1H), 4.32 (s, 1H), 3.46 (t, J=4.6 Hz, 2H),3.46 (t, J=4.6 Hz, 2H), 1.55 (s, 2H), 1.21 (s, 2H).

Tert-butyl3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate,Intermediate AG

Step a:

The mixture of 1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine (100 mg,494 μmol, Intermediate E), Boc₂O (322 mg, 1.48 mmol) and TEA (149 mg,1.48 mmol) in DCM (3 mL) was stirred at 30° C. for 2 hours. Then themixture was concentrated under reduced pressure. The residue waspurified by column chromatography (petroleum ether/ethylacetate=1:0˜10:1) to afford tert-butyl3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(30 mg, 62% purity, 15% yield) as a colorless oil. LCMS m/z[M+Na]⁺=425.1.

Tert-butyl6-bromo-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate,Intermediate AH

Step a:

A solution of tert-butyl6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.5 g, 3.94 mmol, synthesized via Steps a-c of Intermediate AL), AcONH₄(3.03 g, 39.4 mmol) and NaBH₃CN (297 mg, 4.72 mmol) in EtOH (30 mL) wasstirred at 80° C. for 1 h. Then to the mixture was added additionalAcONH₄ (3.03 g, 39.4 mmol) and NaBH3CN (297 mg, 4.72 mmol) 3 times everyhour and the mixture was stirred at 80° C., then the mixture was stirredat 80° C. for 9 h. The solution was added into 10% NaOH (150 mL) andthen extracted with EtOAc (200 mL×2). The combined organic layers werewashed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give tert-butyl1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.5 g, quant. crude yield) as a yellow gum. LCMS m/z[M+H]⁺=381.0/383.0.

Step b:

A solution of tert-butyl1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.5 g, 3.93 mmol), Boc₂O (1.02 g, 4.71 mmol) and Et₃N (1.61 mL, 11.7mmol) in DCM (30 mL) was stirred at 20° C. for 1 h. The solution wasadded into H₂O (100 mL) and then extracted with CH₂Cl₂ (50 mL×2). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give crudeproduct as yellow gum. The residue was purified by flash silica gelchromatography (40 g, Ethyl acetate in Petroleum ether from 0% to 10%)to give tert-butyl6-bromo-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.4 g, 74%) as a yellow gum. LCMS m/z [M+H−100]=381.0/383.0.

1-amino-N,N-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carboxamide,Intermediate AI

Step a:

A solution of tert-butyl6-bromo-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(300.0 mg, 623.0 μmol), Pd(dppf)Cl₂ (45.6 mg, 62.3 umol) and TEA (256.0uL, 1.86 mmol) in MeOH (20.0 mL) was stirred at 80° C. for 12 hoursunder CO (50 psi). The mixture was concentrated to give a residue, whichwas purified by flash silica gel chromatography (12 g, ethyl acetate inpetroleum ether from 0% to 15%) to give 1′-tert-butyl 5-methyl(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′,5-dicarboxylate(200.0 mg, 70% yield) as a white solid. LCMS m/z [M+H]⁺=461.2.

Step b:

A solution of 1′-tert-butyl 5-methyl(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′,5-dicarboxylate(200.0 mg, 434.0 μmol) and LiOH H₂O (91.1 mg, 2.17 mmol) in MeOH/H₂O(3.0 mL/3.0 mL) was stirred at 50° C. for 0.5 hour. The reaction mixturewas adjusted pH=4 with 2 N HCl and extracted with CH₂C2 (10.0 mL×2). Thecombined organic layers were concentrated under reduced pressure to givethe product of1′-[(tert-butoxy)carbonyl]-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-5-carboxylic acid (150.0 mg, 78% yield) as ayellow oil. LCMS m/z [M+H]⁺=447.2.

Step c:

A solution of1′-[(tert-butoxy)carbonyl]-1-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carboxylicacid (200.0 mg, 447.0 μmol), dimethylamine hydrochloride (109.0 mg, 1.34mmol), HATU (254.0 mg, 670.0 umol) and TEA (245.0 uL, 1.78 mmol) in DMF(5.0 mL) was stirred at 50° C. for 0.5 hour. The reaction mixture waspoured into H₂O (20.0 mL) and extracted with EtOAc (20.0 mL×2). Thecombined organic layers were washed with brine (20.0 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive the product of tert-butyl1-{[(tert-butoxy)carbonyl]amino}-6-(dimethylcarbamoyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(200.0 mg, 95% yield) as a yellow oil. LCMS m/z [M+H]⁺=474.2.

Step d:

A solution of tert-butyl1-{[(tert-butoxy)carbonyl]amino}-6-(dimethylcarbamoyl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(200.0 mg, 422.0 μmol) in HCl/MeOH (5.0 mL, 4 M) was stirred at 20° C.for 0.5 hour. The reaction mixture was concentrated under reducedpressure to give the product of1-amino-N,N-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carboxamidedihydrochloride (150.0 mg, quant. crude yield) as a yellow oil. LCMS m/z[M+H]⁺=274.1.

Sodium 2-chloro-3-fluoropyridine-4-thiolate, Intermediate AJ

Step a:

To a mixture of 2-chloro-3-fluoro-4-iodopyridine (900 mg, 3.5 mmol) and2-ethylhexyl 3-sulfanylpropanoate (912 mg, 4.2 mmol) in dioxane (10 mL)were added Pd₂(dba)₃ (319 mg, 0.3 mmol), XantPhos (403 mg, 0.7 mmol) andDIPEA (1.8 mL, 10.4 mmol). The reaction mixture was purged with N₂ for 3min and stirred at 100° C. for 12 hours under N₂. The reaction mixturewas concentrated under reduced pressure to give the residue, which waspurified by column chromatography (petroleum ether:ethyl acetate=100:0to 100:10) to give 2-ethylhexyl3-[(2-chloro-3-fluoropyridin-4-yl)sulfanyl]propanoate (410 mg, 34%yield) as a yellow solid. LCMS m/z [M+H]⁺=348.1.

Step b:

A mixture of 2-ethylhexyl3-[(2-chloro-3-fluoropyridin-4-yl)sulfanyl]propanoate (200 mg, 0.6 mmol)and MeONa (37.1 mg, 0.7 mmol) in THE (1.0 mL) was stirred at 20° C. for1 hour. The mixture was diluted with DCM (0.5 mL) and stirred at 0° C.for 30 min. The reaction mixture was filtered and the cake washed withDCM and air dried to give sodium 2-chloro-3-fluoropyridine-4-thiolate asa light yellow solid (80 mg, 75% yield). LCMS m/z [M+H]⁺=164.0.

Methyl 3-chloro-5-methylpyrazine-2-carboxylate, Intermediate AK

Step a:

A mixture of methyl 3,5-dichloropyrazine-2-carboxylate (2.0 g, 9.7 mmol,synthesized via Step a of Intermediate A),trimethyl-1,3,5,2,4,6-trioxatriborinane (2.4 g, 19.3 mmol), Pd(PPh₃)₄(558 mg, 483 μmol) and Cs₂CO₃ (6.3 g, 19.3 mmol) in dioxane (70 mL) wasstirred at 110° C. for 12 hours under N₂ atmosphere. The reactionmixture was concentrated in vacuo to give a residue, which was purifiedby silica gel chromatography (ethyl acetate in petroleum ether=0% to50%) to afford methyl 3-chloro-5-methylpyrazine-2-carboxylate (250 mg,14% yield) as a yellow solid. LCMS m/z [M+H]⁺=187.0.

tert-butyl(1S)-6-bromo-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate,Intermediate AL

Step a:

To a solution of 1-tert-butyl-4-methyl piperidine-1,4-dicarboxylate(10.00 g, 41.10 mmol) in THE (150.0 mL) was added LDA (24.6 mL, 49.3mmol, 2 M) at −78° C. under N₂. The mixture was stirred at −78° C. for 1hour. To the mixture was added 1-bromo-4-(bromomethyl)benzene (10.70 g,43.10 mmol) in THE (50.0 mL) at −78° C. The mixture was then stirred at20° C. for 11 hours under N₂. The reaction mixture was quenched with H₂O(400.0 mL) and extracted with EtOAc (400.0 mL×2). The combined organiclayers were washed with brine (300.0 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a yellow residue. The residue waspurified by flash silica gel chromatography (120 g column, ethyl acetatein petroleum ether from 0% to 5%) to give 1-tert-butyl 4-methyl4-[(4-bromophenyl)methyl]piperidine-1,4-dicarboxylate (11.40 g, 67%yield) as a yellow oil. LCMS m/z [M+H−100]⁺=312.0/314.0.

Step b:

A solution of 1-tert-butyl 4-methyl4-[(4-bromophenyl)methyl]piperidine-1,4-dicarboxylate (11.40 g, 27.6mmol) and KOH (7.74 g, 138.0 mmol) in MeOH/H₂O (50.0 mL/50.0 mL) wasstirred at 60° C. for 16 hours. The mixture was adjusted to pH=5 with 2N HCl and extracted with CH₂Cl₂ (150.0 mL×2). The combined organiclayers were washed with brine (200.0 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give4-[(4-bromophenyl)methyl]-1-[(tert-butoxy)carbonyl]piperidine-4-carboxylicacid (10.8 g, 99% yield) as a white solid. LCMS m/z[M+H−100]⁺=298.0/300.0.

Step c:

To a solution of4-[(4-bromophenyl)methyl]-1-[(tert-butoxy)carbonyl]piperidine-4-carboxylicacid (10.00 g, 25.1 mmol) in DCM (150.0 mL) was added SOCl₂ (3.64 mL,50.2 mmol) at 20° C. under N₂. The mixture was stirred at 20° C. for 1hour, where a white suspension was observed. To the mixture was addedAlCl₃ (5.01 g, 37.6 mmol) in portions at 0° C. The mixture was stirredat 20° C. for 2 h under N₂. The reaction mixture was then quenched by 2N NaOH and adjusted pH=10. Next, to the mixture was added Boc₂O (10.90g, 50.2 mmol) at 20° C. The mixture was stirred at 20° C. for 1 hour.The reaction mixture was filtered and the filtrate was extracted withCH₂Cl₂ (100.0 mL×2). The combined organic layers were washed with brine(200.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated togive a yellow residue. The residue was purified by flash silica gelchromatography (80 g column, ethyl acetate in petroleum ether from 0% to10%) to give tert-butyl6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(6.00 g, 63% yield) as an orange solid. LCMS m/z [M+H−100]=280.0/282.0.

Step d:

To a solution of tert-butyl6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.00 g, 2.62 mmol) and Ti(OEt)₄ (2.17 mL, 10.4 mmol) in 2-Me-THF (20.0mL) was added (R)-2-methylpropane-2-sulfinamide (635.0 mg, 5.24 mmol).The reaction mixture was stirred at 90° C. for 12 hours under N₂.Tert-butyl(1E)-6-bromo-1-{[(R)-2-methylpropane-2-sulfinyl]imino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.30 g, crude) in 2-Me-THF (20.0 mL) was used directly in the next stepwithout further purification.

Step e:

To a solution of tert-butyl(1E)-6-bromo-1-{[(R)-2-methylpropane-2-sulfinyl]imino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.30 g, 2.68 mmol) in 2-Me-THF (20.0 mL) was added LiBH₄ (2.68 mL, 5.36mmol) at 0° C. The mixture was stirred at 20° C. for 1 hour. Thereaction mixture was quenched with MeOH, then triturated with H₂O (200.0mL) and extracted with EtOAc (200.0 mL×2). The combined organic layerswere washed with brine (200.0 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give an orange residue. The residue was purified byflash silica gel chromatography (40 g column, ethyl acetate in petroleumether from 0% to 30%) to give tert-butyl(1S)-6-bromo-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(550.0 mg, 42% yield) as a white solid. LCMS m/z [M+H]⁺=485.1/487.1.

(S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile,Intermediate AM

Step a:

A solution of tert-butyl(1S)-6-bromo-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(550.0 mg, 1.13 mmol, Intermediate AL), Zn(CN)₂ (265.0 mg, 2.26 mmol)and XantPhos-Pd-G4 (108.0 mg, 113.0 umol) in DMF (20.0 mL) was stirredat 100° C. for 12 hours under N₂. The reaction mixture was poured intoH₂O (100.0 mL) and extracted with EtOAc (100.0 mL×2). The combinedorganic layers were washed with brine (200.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give an orange residue. The residuewas purified by flash silica gel chromatography (12 g column, ethylacetate in petroleum ether from 0% to 50%) to give tert-butyl(1S)-6-cyano-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(490.0 mg, 100% yield) as a white solid. LCMS m/z [M+H]⁺=432.2.

Step b:

A solution of tert-butyl(1S)-6-cyano-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(450.0 mg, 1.04 mmol) in HCl/MeOH (15.0 mL, 4 M) was stirred at 20° C.for 0.5 hour. The reaction mixture was concentrated to give the productof (S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitriledihydrochloride (450.0 mg, 70% purity, quant. crude yield) as a whitesolid. LCMS m/z [M+H]⁺=228.1.

7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline, Intermediate AN

Step a:

To the mixture of 4-bromo-2-fluoro-1-nitrobenzene (25.0 g, 113.0 mmol)in MeOH (100.0 mL) and THF (50.0 mL) was added MeNH₂ (67.5 mL, 135.0mmol, 2 M in THF) dropwise. The mixture was stirred at 10° C. for 12hours. Then more MeNH₂ (60.0 mL, 2 M in THF) was added to the mixtureand the mixture was stirred at 45° C. for 12 hours. The mixture wasconcentrated in vacuo to give residue. Water (200.0 mL) added to themixture and the mixture was extracted with EtOAc (200.0 mL×2). Theorganic layers were washed with brine and dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated in vacuo to give5-bromo-N-methyl-2-nitroaniline (25.5 g, 98% yield) as a yellow solid.¹HNMR (400 MHz, CDCl₃) 7.95 (d, J=9.2 Hz, 2H), 6.93 (d, J=1.6 Hz, 1H),6.71-6.68 (m, 1H), 7.48 (s, 1H), 2.94 (d, J=5.2 Hz, 3H).

Step b:

To the mixture of 5-bromo-N-methyl-2-nitroaniline (10.0 g, 43.2 mmol) inMeOH (150.0 mL) was added sodium dithionite (67.5 g, 388.0 mmol) in H₂O(60.0 mL) dropwise. The mixture was stirred at 60° C. for 12 hours. Themixture was then filtered and the filtrate was concentrated in vacuo.The residue was extracted with EtOAc (200.0 mL×3), the organic layerswere washed with H₂O (100.0 mL) and brine (100.0 mL), then dried overanhydrous Na₂SO₄. The mixture was filtered and the filtrate wasconcentrated in vacuo to give the product of5-bromo-N1-methylbenzene-1,2-diamine (8.60 g, crude) as a brown oil.

Step c:

A mixture of 5-bromo-N1-methylbenzene-1,2-diamine (1.0 g, 4.97 mmol),1,2-dibromoethane (2.13 mL, 24.8 mmol) and TBAB (4.80 g, 14.9 mmol) wasstirred at 60° C. for 12 hours. The mixture was concentrated in vacuoand purified by flash silica gel chromatography (petroleumether/EtOAc=1/0 to 2/1) to give7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (233.0 mg, 21% yield) asa brown solid. LCMS m/z [M+H]⁺=226.9/228.9.

4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Intermediate AO

Step a:

To the mixture of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (500.0mg, 2.20 mmol) and Zn(CN)₂ (516.0 mg, 4.40 mmol) in DMF (10.0 mL) wasadded [(t-Bu)₃P]₂Pd (224.0 mg, 440.0 μmol) under N₂. The mixture wasstirred at 120° C. under N₂ for 12 hours. TLC (petroleumether/EtOAc=2/1) showed a new spot formed and no starting materialremained. The combined mixture was poured into water (50.0 mL) andextracted with EtOAc (50.0 mL×3). The combined organic layers werewashed with brine (50.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduce pressure to give a brown residue. The residuewas purified by flash silica gel chromatography (petroleumether/EtOAc=1/0 to 2/1) to give the product of4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (370.0 mg, 95.0%purity) as a brown solid. LCMS m/z [M]⁺=173.8.

3H-spiro[1-benzofuran-2,4′-piperidin]-3-one, Intermediate AP

Step a:

To a solution of 2-fluorobenzaldehyde (4 g, 32.2 mmol) in DCM (20 mL)were added propane-1, 3-dithiol (3.5 mg, 32.2 mmol) and I₂ (244 mg, 966umol). The mixture was stirred at 25° C. for 12 hours. The reactionmixture was poured into the solution of Na₂S203 (0.4 M, 180 mL) and 150mL of NaOH solution was added. The organic phase was separated and theaqueous phase was extracted with CH₂Cl₂ (200 mL). The combined organicfractions were washed with water (150 mL), brine (150 mL), dried overanhydrous Na₂SO₄, then filtered and evaporated under reduced pressure togive a yellow solid. Recrystallisation from CH₂Cl₂:petroleum ether (1:1)afforded 2-(2-fluorophenyl)-1,3-dithiane (5.00 g, 72% yield) as a whitesolid. LCMS m/z [M+H]⁺=215.0.

Step b:

To a mixture of 2-(2-fluorophenyl)-1,3-dithiane (4 g, 18.6 mmol) in THE(50 mL) was added LDA (18.6 mL, 37.2 mmol) at −78° C. slowly. Theresulting mixture was stirred at −20° C. for 0.5 hour, then tert-butyl4-oxopiperidine-1-carboxylate (3.7 g, 18.6 mmol) was added at −78° C.The reaction mixture was stirred at −78° C. for 2 hours. The reactionmixture was then poured into saturated NH₄Cl (50 mL) and extracted withEtOAc (80 mL×3). The combined organic fractions were washed with water(100 mL), brine (100 mL), dried over Na₂SO₄, then filtered andevaporated under reduced pressure to give a yellow oil. The oil waspurified by silica gel column (elution: petroleum ether:ethylacetate=5:1˜2:1) to give the product of tert-butyl4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate(3.20 g, 42% yield) as a white solid. LCMS m/z [M-100]⁺=313.9.

Step c:

A mixture of tert-butyl4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate(2 g, 4.83 mmol) in DCM (20 mL) and H₂O (5 mL) were added pyridine (2mL), pyridine HBr₃ (1.82 g, 5.79 mmol) and TBAB (158 mg, 483 umol). Themixture was stirred at 25° C. for 12 hours. The solution was poured intowater (30 mL) and extracted with DCM (50 mL×3). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, thenfiltered and evaporated under reduced pressure. The crude product waspurified by silica gel column (elution: petroleum ether:ethylacetate=5:1˜1:1) to give tert-butyl4-(2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (1.20 g, 77%yield) as a yellow solid. LCMS m/z [M−100]⁺=223.9.

Step d:

To a solution of tert-butyl4-(2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (600 mg, 1.85mmol) in dioxane (5 mL) was added t-BuOK (207 mg, 1.85 mmol). Themixture was stirred at 70° C. for 2 hours. The mixture was concentratedunder reduced pressure and diluted with water (20 mL), extracted byEtOAc (30 mL×3). The combined organic layers were washed with brine(30.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (petroleum ether:ethyl acetate=100:0 to 100:10) to givetert-butyl 3-oxo-3H-spiro[1-benzofuran-2,4 (210 mg, 75% yield) as awhite solid. LCMS m/z [M−100]⁺=203.9.

Step e:

To a solution of tert-butyl3-oxo-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-carboxylate (300 mg, 988μmol) in dioxane (2 mL) was added HCl/dioxane (2.46 mL, 4M). The mixturewas stirred at 20° C. for 12 hours. The reaction mixture wasconcentrated to dryness, MeOH (2 mL) and K₂CO₃ (100 mg) were added. Themixture was filtered and the filtrate was concentrated to dryness togive 3H-spiro[1-benzofuran-2,4′-piperidin]-3-one (150 mg, 75% yield) asa white solid. LCMS m/z [M+H]⁺=204.9.

6-methyl-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one, Intermediate AQ

Step a:

6-methyl-1,6-naphthyridin-6-ium iodide (1.56 g, 5.73 mmol, CAS#37960-58-0) was suspended in water (10 mL) and cooled to 0° C. Thereaction was charged with sodium hydroxide (1.25 g, 31.5 mmol) in water(10 mL) and tripotassium hexakis(iminomethanide) iron (4.04 g, 12.3mmol) in water (10 mL). The solution was stirred for 1 hr at 0° C., then16 hr at rt. The mixture was extracted with CHCl₃, dried andpre-absorbed on SiO₂ (3 g). The residue was purified by columnchromatography (Si-40 g column, 0-10% MeOH/DCM) to give6-methyl-1,6-naphthyridin-5(6H)-one (540 mg, 59% yield) as a lightyellow solid. LCMS m/z [M+H]⁺=161.1; ¹H NMR (400 MHz, CHLOROFORM-d) δ8.90 (dd, J=1.89, 4.67 Hz, 1H), 8.71 (dd, J=1.26, 8.08 Hz, 1H), 7.42(dd, J=4.55, 8.08 Hz, 1H), 7.32 (d, J=7.58 Hz, 1H), 6.79 (d, J=7.58 Hz,1H), 3.63 (s, 3H).

Step b:

6-methyl-5,6-dihydro-1,6-naphthyridin-5-one (109 mg, 0.6805 mmol) wasdissolved in MeOH (10 mL). The solution was cycled through the H-Cube, 1mL/min, 10% Pd/C, 70 bar, 70° C. After 1 h, the solvent was removed andresidue chased with DCM to give6-methyl-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one (105 mg, 94%yield) as a white solid. LCMS m/z [M+H]⁺=165.0.

(R)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate AR, and(S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate AS

(R)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine and(S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine wassynthesized as described above for Intermediate T, using2-bromo-1-(bromomethyl)-3-fluorobenzene as the coupling partner in Stepa. In Step c, (R)-2-methylpropane-2-sulfinamide was utilized and amixture of diastereomers was formed during the reduction, which wereseparable by prep-HPLC to give tert-butyl(R)-1-(((S)-tert-butylsulfinyl)amino)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(earlier eluting isomer, ¹H NMR (400 MHz, DMSO-d6) δ 7.26 (dt, J=5.25,7.75 Hz, 1H), 7.04 (d, J=7.57 Hz, 1H), 6.95 (t, J=8.79 Hz, 1H), 5.68 (d,J=9.77 Hz, 1H), 4.44 (d, J=10.01 Hz, 1H), 3.78 (br d, J=11.96 Hz, 1H),3.59-3.72 (m, 1H), 3.00 (br d, J=16.11 Hz, 3H), 2.77 (br d, J=16.11 Hz,1H), 1.71 (br t, J=10.25 Hz, 1H), 1.34-1.56 (m, 11H), 1.21-1.31 (m, 1H),1.10 (s, 9H)) and tert-butyl(S)-1-(((R)-tert-butylsulfinyl)amino)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(later eluting isomer, ¹H NMR (400 MHz, DMSO-d6) δ 7.27 (dt, J=5.25,7.75 Hz, 1H), 7.05 (d, J=7.32 Hz, 1H), 6.95 (t, J=8.67 Hz, 1H), 5.51 (d,J=7.57 Hz, 1H), 4.38 (d, J=7.57 Hz, 1H), 3.52-3.72 (m, 2H), 2.95-3.19(m, 3H), 2.80 (br d, J=15.87 Hz, 1H), 1.59-1.74 (m, 2H), 1.38 (s, 9H),1.18-1.33 (m, 2H), 1.08 (s, 9H)). Characterization of(R)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine &(S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine: LCMS m/z[M+H]⁺ for both enantiomers=221.1.

5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-amine,Intermediate AT

Step a:

tert-butyl 4-cyanopiperidine-1-carboxylate (1.65 g, 7.84 mmol) in THE(10 mL) was cooled to −78° C. and charged withlithiobis(propan-2-yl)amine (9.01 mL, 9.01 mmol) (max temperature −65°C. on addition) and the reaction was stirred at −78° C. for 1.5 hr. Thena solution of 2-bromo-3-(bromomethyl)pyridine (1.93 g, 7.72 mmol)(caution, material is very irritant) in THF (2 mL) with a few drops ofDMF to improve solubility, was added and the reaction stirred at −78° C.for 2 h. Then the reaction was allowed to warm to 0° C. then to rt andthe reaction was stirred for 16 hr. The reaction was diluted with waterand EA. The org layer pre-absorbed on SiO₂ (7 g) and purified by columnchromatography (Si-80 g column, 25-50% EA/Hep) to give tert-butyl4-((2-bromopyridin-3-yl)methyl)-4-cyanopiperidine-1-carboxylate (910 mg,31% yield) as a colorless oil that solidified to a waxy solid uponstanding. LCMS m/z [M-tBu]⁺=324.0/326.0.

Step b:

tert-butyl4-[(2-bromopyridin-3-yl)methyl]-4-cyanopiperidine-1-carboxylate (910 mg,2.39 mmol) in 2-MeTHF (15 mL) was cooled to 0° C. and charged withchloro(propan-2-yl)magnesium; chlorolithium (3.67 mL, 4.78 mmol) and thereaction was stirred at 0° C. for 30 min. Next, the reaction was cooledto −78° C. and charged with butyllithium (1.04 mL, 2.62 mmol) and thereaction was stirred for 1 hr at −78° C. Then an additional 0.25 eq. ofnBuLi was added and the reaction was stirred for 45 min more. Thereaction mixture was then quenched with water and extracted with EA(2×). The organic layer was dried and concentrated to give tert-butyl7-imino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(700 mg, 97% yield). LCMS m/z [M+H]⁺=246.0/302.0.

Step c:

tert-butyl7-imino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(720 mg, 2.38 mmol) was dissolved in EA (15 mL) and run in a H-Cube for90 min (5 bar, 40° C.). The solvent was then removed by rotaryevaporation and the crude residue was purified by prep-HPLC (5-40%ACN/water/FA). tert-butyl7-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(208 mg, 29% yield). ¹H NMR (400 MHz, DMSO-d6) δ 8.32-8.43 (m, 1H), 8.21(s, 1H), 7.56-7.69 (m, 1H), 7.13-7.27 (m, 1H), 3.94 (s, 1H), 3.74 (br d,J=12.94 Hz, 2H), 2.99 (br d, J=16.11 Hz, 3H), 2.62 (br d, J=16.11 Hz,1H), 2.45-2.51 (m, 3H), 1.49-1.71 (m, 2H), 1.31-1.48 (m, 8H), 1.04 (brd, J=13.43 Hz, 1H). Side product tert-butyl7-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(100 mg) was also isolated. ¹H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=3.66Hz, 1H), 8.07 (d, J=7.81 Hz, 1H), 7.62 (dd, J=4.64, 7.81 Hz, 1H), 3.93(br d, J=12.94 Hz, 2H), 3.11 (s, 2H), 2.99 (br s, 2H), 1.59 (dt, J=4.27,12.63 Hz, 2H), 1.30-1.52 (m, 10H).

Step d:

tert-butyl7-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(208 mg, 0.6855 mmol) in MeOH (5 mL) was charged with hydrogen chloride(1.71 mL, 6.85 mmol) and the reaction was stirred at rt for 2.5 h. Thenthe reaction was heated to 50° C. for 5 h. The reaction was cooled to rtand stirred for 16 h. The solvent was then removed by rotary evaporationand chased with MTBE to yield5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-aminedihydrochloride (188 mg, 99% yield) as a white solid. LCMS m/z[M+H]⁺=204.0.

tert-butyl(1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-yl)carbamate,Intermediate AU

Step a:

6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (244 mg, 0.6697mmol, Intermediate A) in DMF (4 mL) was charged withethylbis(propan-2-yl)amine (580 μL, 3.34 mmol) and5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-aminedihydrochloride (185 mg, 0.6697 mmol, Intermediate AT) and the solutionwas heated to 80° C. for 4 h. Then the reaction was cooled to rt anddi-tert-butyl dicarbonate (175 mg, 0.8036 mmol) was added and thereaction was stirred at rt for 16 h. Then an additional 0.25 eq ofdi-tert-butyl dicarbonate was added and the reaction was stirred for anadditional 2.5 hr at rt. The reaction mixture was then partitionedbetween brine and EA. The organic layer was pre-absorbed on SiO₂ (2 g)and the mixture was purified by column chromatography (Si 12 g column,70-100% EA/hep) to give tert-butyl(1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-yl)carbamate(260 mg, 73% yield) as a yellow solid. LCMS m/z [M+H]⁺=632.1.

Sodium 2,3-dichloropyridine-4-thiolate, Intermediate AV

Step a:

To a solution of 2,3-dichloro-4-iodopyridine (2 g, 7.30 mmol) and2-ethylhexyl 3-sulfanylpropanoate (1.75 g, 8.01 mmol) in dioxane (20 mL)was added XantPhos (844 mg, 1.46 mmol), Pd₂dba₃ (668 mg, 0.7300 mmol)and DIPEA (3.81 mL, 21.9 mmol). Then the mixture was stirred at 100° C.for 12 h under N₂. Brine and EtOAc were then added to the reactionmixture, which was then extracted with EtOAc (3×). The combined organiclayer was dried over Na2SO4, filtered and evaporated down with SiO2. Themixture was purified by column chromatography (6-50% EtOAc in hexanes)to give 2-ethylhexyl 3-((2,3-dichloropyridin-4-yl)thio)propanoate (1.6g, 60% yield). LCMS m/z [M+H]⁺=363.9/365.9.

Step b:

2-ethylhexyl 3-[(2,3-dichloropyridin-4-yl)sulfanyl]propanoate (307 mg,0.8426 mmol) was dissolved in THE (0.3M, 2.8 mL) and ethoxysodium (329μL, 0.8847 mmol, 21% in EtOH) was added and the reaction was stirred atrt for 10 min. The mixture was diluted with DCM (10-15 mL) and stirreduntil nucleation occurred; after 5 min a large amount of solid formed insuspension. The mixture was filtered to give(2,3-dichloropyridin-4-yl)sulfanide (79 mg, 46% yield). LCMS m/z[M+H-Na]⁺=179.9/181.9.

Sodium 3-chloro-2-methylpyridine-4-thiolate, Intermediate AW

Step a:

To a solution of 2-ethylhexyl3-[(2,3-dichloropyridin-4-yl)sulfanyl]propanoate (800 mg, 2.19 mmol,synthesized via Step a of Intermediate AV) and trimethylboroxine (411mg, 3.28 mmol) in dioxane (0.3M, 7 mL) and water (4M, 0.5 mL) was addedXphosG4 (376 mg, 0.438 mmol) and Pd₂dba₃ (376 mg, 0.438 mmol). Themixture was degassed for 3 min then heated to 110° C. for 2 h. Themixture was then cooled to rt, and EtOAc and brine were added. Themixture was extract with EtOAc, and the organic layer was dried overNa₂SO, filtered and concentrated in vacuo. The residue was purified viacolumn chromatography (40 g column, 0-60% EtOAc) to give 2-ethylhexyl3-((3-chloro-2-methylpyridin-4-yl)thio)propanoate (317 mg. 42% yield).LCMS m/z [M]⁺=343.9.

Step b:

2-ethylhexyl 3-[(3-chloro-2-methylpyridin-4-yl)sulfanyl]propanoate (317mg, 0.922 mmol) was dissolved in THE (0.3M, 3 mL) and ethoxysodium (360μL, 0.968 mmol) [21% in EtOH] was added and the mixture was stirred atrt for 10 min. The mixture was diluted with DCM (10-15 mL) and stirreduntil nucleation occurred. After 5 min, large amount of solid formed inthe suspension. The mixture was filtered to yield(3-chloro-2-methylpyridin-4-yl)sulfanide (146 mg, quan. yield). LCMS m/z[M+H-Na]⁺=159.9/161.9.

tert-butyl((3S)-4-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate,Intermediate AX

Step a:

6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (91.9 mg, 0.252mmol, Intermediate A) in DMF (4 mL) was charged withethylbis(propan-2-yl)amine (218 μL, 1.26 mmol) and(S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (74 mg, 0.252 mmol, Intermediate AS) and the solutionwas heated to 80° C. for 3 hr. The reaction was cooled to rt anddi-tert-butyl dicarbonate (66.0 mg, 0.303 mmol) was added and thereaction was stirred for 16 hr at rt. Then 0.25 eq more of di-tert-butyldicarbonate was added and the reaction was stirred for an additional 2.5h. The reaction was then partitioned between brine and EA. The organiclayer was pre-absorbed on SiO₂ (2 g) and purified by columnchromatography (Si-12 g column, 20-70% EA/hep) to give tert-butyl((3S)-4-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(90 mg, 55% yield) as a white solid. LCMS m/z [M+Na]⁺=671.1.

(S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine,Intermediate AY

(S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine wassynthesized as described for Intermediate T, using3-bromo-2-(bromomethyl)pyridine as the coupling partner in Step a. LCMSm/z [M+H]⁺=204.1.

tert-butylN-[(5S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl]carbamate,Intermediate AZ

Step a:

Dissolved 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (223mg, 0.6118 mmol, Intermediate A) in DMF (5 mL). Next,(5S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-aminedihydrochloride (169 mg, 0.6118 mmol, Intermediate AY) was addedfollowed by ethylbis(propan-2-yl)amine (425 μL, 2.44 mmol) and thereaction was stirred at 75° C. for 2 h. Next, di-tert-butyl dicarbonate(153 μL, 0.6729 mmol) was added and the reaction was stirred at rt for1.5 hr. The reaction mixture was then diluted with EtOAc and extractedwith water. The layers were separated, and the organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated onto SiO₂. Themixture was purified by column chromatography (0-100% EtOAc in heptanes)to give tert-butylN-[(5S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl]carbamate(167 mg, 43% yield). LCMS m/z [M+H]⁺=632.1.

spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine, Intermediate AB

Step a:

Dry DMSO (5 mL) was added to a 50 mL flask, which was then bubbled withN₂ gas and equipped with a thermocouple. To the solution was addedsodium hydride (173 mg, 4.36 mmol, 60% in oil) in small portions whilethe temperature was monitored so as not to exceed 35° C. Thentrimethyl(oxo)-λ⁶-sulfanylium iodide (959 mg, 4.36 mmol) was added insmall portions while monitoring temperature. The suspension was thenstirred at rt for 45 min. Meanwhile, tert-butyl1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (1 g, 3.97 mmol,synthesized as described in PCT Int. Appl., 2016203406) was dissolved in2.5 mL dry DMSO. This solution was then added dropwise to reactionmixture while stirring vigorously and monitoring temperature so as notto exceed 27° C. The reaction mixture was then stirred at rt for 16 h.Then 10 mL of water was added dropwise and the solution was extractedwith diethyl ether (2×30 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (0-100% EtOAc in heptanes) to give tert-butyl4-oxospiro[bicyclo[3.1.0]hexane-3,4′-piperidine]-1′-carboxylate (422 mg,40% yield) as a colorless oil. LCMS m/z [M+H−100]=166.0.

Step b:

Dissolved hydrogen chloride (288 mg, 7.91 mmol) in EtOH (15 mL), thenadded tert-butyl 4-oxospiro[bicyclo[3.1.0]hexane-3,4 (210 mg, 0.791mmol) followed by acetic acid amine (909 mg, 11.8 mmol) and NaCNBH₃(54.6 mg, 0.870 mmol). The reaction mixture was then heated in amicrowave at 130° C. for 1 h. Additional NaCNBH₃ (54.6 mg, 0.870 mmol)was added and the mixture was stirred in a microwave at 130° C. for 1 hmore. The reaction mixture was then concentrated in vacuo and theresidue was treated with NaOH (2N, 15 mL). The mixture was extractedwith EtOAc (2×5 mL), and the combined organic layer was dried overNa₂SO₄. The solution was concentrated in vacuo and purified by columnchromatography (0-100% EtOAc in heptanes, followed by 0-10% MeOH in DCMw/ 0.1% NH₄OH, where product eluted at ˜7% MeOH) give tert-butyl4-aminospiro[bicyclo[3.1.0]hexane-3,4 (70.0 mg, 33% yield). LCMS m/z[M+H−56]⁺=211.1.

Step c:

Dissolved tert-butyl 4-aminospiro[bicyclo[3.1.0]hexane-3,4 (70.0 mg,0.26 mmol) in 3 mL MeOH. Then HCl (4N in dioxanes, 1 mL) was added andthe reaction mixture was stirred at rt for 16 h. The reaction mixturewas then concentrated in vacuo and chased with MeOH to givespiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-4-amine dihydrochloride (76.0mg, quant. crude yield). LCMS m/z [M+H]⁺=167.0.

tert-butyl(1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate,Intermediate BB

Step a:

Spiro[bicyclo[3.1.0]hexane-3,4 (120 mg, 0.502 mmol, Intermediate BA) and6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (182 mg, 0.502mmol, Intermediate A) were placed into a round bottom flask anddissolved in DMF (2 mL). Then ethylbis(propan-2-yl)amine (435 μL, 2.50mmol) was added and the reaction mixture was stirred at rt for 2 h.Next, di-tert-butyl dicarbonate (114 μL, 0.502 mmol) was added and thereaction mixture was stirred at rt from 2.5 h. The reaction mixture wasthen concentrated in vacuo and purified by column chromatography (0-100%EtOAc in heptanes) to give tert-butyl(1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(185 mg, 62% yield). LCMS m/z [M]⁺=594.3.

(S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-amine,Intermediate BC

(S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-amine wassynthesized as described for Intermediate T and Intermediate AY,coupling (3-bromopyridin-4-yl)methyl methanesulfonate in Step a. LCMSm/z [M+H]⁺=204.1.

tert-butylN-[(7R)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-yl]carbamate,Intermediate BD

tert-butylN-[(7R)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-yl]carbamate was synthesized asdescribed for Intermediate AZ, coupling6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (IntermediateA) and(S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-aminedihydrochloride (Intermediate BC) in Step a. LCMS m/z [M+H]⁺=632.1.

tert-butylN-[(3S)-1′-{3-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate BE

Step a:

The mixture of methyl 3,5-dichloropyrazine-2-carboxylate (1.0 g, 4.83mmol, CAS #330786-09-9),(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(1.65 g, 4.83 mmol, Intermediate I) and CsF (3.66 g, 24.1 mmol) in DMF(15 mL) was stirred at 70° C. for 2 hours. Boc₂O (1.57 g, 7.24 mmol) andTEA (1 mL) were then added to the mixture and the mixture was stirred at20° C. for 1 hour. The mixture was diluted with H₂O (50 mL), andextracted with EtOAc (50 mL×2). The organic layer was washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(petroleum ether/ethyl acetate=1:0˜5:1) to afford methyl5-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-chloropyrazine-2-carboxylate(1.58 g, 69% yield) as a yellow solid. LCMS m/z [M+H]⁺=473.1.

Step b:

The mixture of methyl5-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-chloropyrazine-2-carboxylate(1.5 g, 3.17 mmol), PMBNHNH₂.2HCl (927 mg, 4.12 mmol) and TEA (2.01 mL,15.8 mmol) in EtOH (20 mL) was stirred at 80° C. for 10 hours. Themixture was concentrated under reduced pressure and the residue waspurified by column chromatography (DCM/MeOH=1:0˜10:1) to affordtert-butylN-[(3S)-1′-{3-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(2.6 g, quant. crude yield) as a yellow solid. LCMS m/z [M+H]⁺=557.2.

tert-butyl(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-bromopyrazin-2-yl)carbamateand tert-butyl(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-bromopyrazin-2-yl)(tert-butoxycarbonyl)carbamate(mixture), Intermediate BF

Step a:

A mixture of 3-bromo-6-chloropyrazin-2-amine (300 mg, 1.4 mmol, CAS#212779-21-0), DMAP (87 mg, 0.7 mmol) and (Boc)₂O (936 mg, 4.3 mmol) inDCM (15 mL) was stirred at 25° C. for 16 h. The reaction mixture wasthen washed with H₂O (15 mL×2) and brine (15 mL). The organic phase wasdried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:0 to 100:10) to afford tert-butylN-(3-bromo-6-chloropyrazin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (580mg, 99% yield) as a white solid. LCMS m/z [M+Na]⁺=429.8/431.8.

Step b:

tert-butylN-(3-bromo-6-chloropyrazin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (270mg, 0.7 mmol), (3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine (200mg, 1.0 mmol, Intermediate I) and DIPEA (0.3 mL, 2.0 mmol) were addedinto DMF (2 mL). The mixture was stirred at 85° C. for 12 h. Thereaction mixture was then diluted with EtOAc (50 mL). The mixture waswashed with H₂O (15 mL×3) and brine (15 mL×3), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (DCM:MeOH=100:5) to affordthe mixture of tert-butyl(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-bromopyrazin-2-yl)carbamateand tert-butyl(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-bromopyrazin-2-yl)(tert-butoxycarbonyl)carbamate(200 mg) as a yellow oil. LCMS m/z [M+H]⁺=474.4/476.1; 574.1/576.1.

2-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-f]quinolin-3-one,Intermediate BG

Step a:

A mixture of 5-bromoquinoline (2.0 g, 9.61 mmol, 1.0 eq), Zn(CN)₂ (2.26g, 19.23 mmol, 2.0 eq) and XantPhos-Pd-G4 (924.8 mg, 961.3 umol, 0.1 eq)in dioxane (20.0 mL) and H₂O (2.0 mL) was stirred at 80° C. for 16 hoursunder N₂. The reaction mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (petroleumether/ethyl acetate=0.1) to afford quinoline-5-carbonitrile (1.28 g,84.6% yield) as a white solid. LCMS m/z [M+H]⁺=155.1.

Step b:

To a solution of quinoline-5-carbonitrile (780.0 mg, 5.06 mmol, 1.0 eq)in MeOH (10.0 mL) were added Raney-Ni (300.0 mg, 5.11 mmol, 1.0 eq) andNH₃.H₂O (1.91 g, 2.10 mL, 28% solution). The reaction mixture wasdegassed and refilled with H₂ for three times. The reaction mixture wasstirred at 15° C. for 16 hours under H₂ (15 psi). The reaction mixturewas filtered through a pad of celite and washed with MeOH (5.0 mL×4).The filtrate was concentrated under reduced pressure to give a greenresidue. The residue was purified by silica gel column chromatography(DCM:MeOH=10:1) to afford 5-quinolylmethanamine (550.0 mg, 69% yield) asa green oil. LCMS m/z [M]⁺=158.1.

Step c:

To a solution of 5-quinolylmethanamine (550.0 mg, 3.48 mmol, 1.0 eq) inDCM (7.0 mL) were added isopropyl carbonochloridate (852.1 mg, 6.95mmol, 965.0 uL, 2.0 eq) and TEA (1.06 g, 10.43 mmol, 1.45 mL, 3.0 eq).The reaction mixture was stirred at 15° C. for 16 hours under N₂. Thereaction mixture was concentrated under reduced pressure to give ayellow residue. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=0:1) to afford isopropylN-(5-quinolylmethyl)carbamate (670.0 mg, 79% yield) as a white solid.LCMS m/z [M+H]⁺=245.1.

Step d:

To a solution of isopropyl-N-(5-quinolylmethyl)carbamate (830.0 mg, 3.40mmol, 1.0 eq) and Cs₂CO₃ (3.32 g, 10.19 mmol, 3.0 eq) in DMF (10.0 mL)was added a solution of Mel (578.7 mg, 4.08 mmol, 253.8 uL, 1.2 eq) inDMF (2.0 mL). The reaction mixture was stirred at 15° C. for 16 hoursunder N₂. The reaction mixture was concentrated under reduced pressure.The residue was washed with water (70.0 mL) and extracted with EtOAc(50.0 mL×3). The combined organic layer was concentrated under reducedpressure to give a red residue. The residue was purified by silica gelcolumn chromatography (DCM:MeOH=10:1) to affordisopropyl-N-methyl-N-(5-quinolylmethyl)carbamate (610.0 mg) as a redoil. The crude product was purified again by silica gel columnchromatography (petroleum ether/rthyl acetate=0:1) to affordisopropyl-N-methyl-N-(5-quinolylmethyl)carbamate (210.0 mg, 24% yield)as a yellow oil. LCMS m/z [M+H]⁺=259.1.

Step e:

To a solution of isopropyl-N-methyl-N-(5-quinolylmethyl)carbamate (130.0mg, 503.3 umol, 1.0 eq) in MeOH (3.0 mL) was added PtO₂ (20.0 mg, 88.08umol, 1.75 eq). The reaction mixture was degassed and refilled with H₂for three times. The reaction mixture was stirred at 30° C. for 16 hoursunder H₂ (15 psi). The reaction mixture was filtered through a pad ofcelite and washed with MeOH (5.0 mL×3). The filtrate was concentratedunder reduced pressure to give the product of isopropylN-methyl-N-(1,2,3,4-tetrahydroquinolin-5-ylmethyl)carbamate (115.0 mg,87% yield) as a green oil. LCMS m/z [M+H]⁺=262.9; ¹HNMR (400 MHz,Methanol-d₄): δ 6.95-6.91 (m, 1H), 6.51 (d, J=8.0 Hz, 1H), 6.43 (d,J=7.2 Hz, 1H), 4.98-4.92 (m, 1H), 4.43 (s, 2H), 3.26-3.23 (m, 2H), 2.84(s, 3H), 2.68-2.65 (m, 2H), 2.00-1.94 (m, 2H), 1.31-1.29 (m, 6H).

Step f:

To a solution of isopropylN-methyl-N-(1,2,3,4-tetrahydroquinolin-5-ylmethyl)carbamate (60.0 mg,228.7 umol, 1.0 eq) in DCM (3.8 mL) was added P₂O₅ (324.6 mg, 2.29 mmol,10.0 eq). The reaction mixture was stirred at 40° C. for 16 hours underN₂. The reaction mixture was adjusted to pH=8 by adding saturated NaHCO₃aqueous solution and extracted with DCM (30.0 mL×2). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give a yellow residue. The crude product waspurified by prep-HPLC (NH₄HCO₃) (column: Waters Xbridge 150×25 5 u;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 15%-45%, 7 min) toafford 2-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-f]quinolin-3-one (20.0mg, 43% yield) as a white solid. LCMS m/z [M+H]⁺=202.9.

(R)—N-[(1S)-7-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide,Intermediate BH

Step a:

A mixture of 2-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol, CAS#53663-39-1), DIPEA (38.2 mL, 232.0 mmol), HATU (22.9 g, 60.4 mmol) andDMF (80.0 mL) was stirred at 25° C. for 1 hour. Then NH₄Cl (7.4 g, 139.0mmol) was added, and the resulting mixture was stirred at 25° C. for 12hours. The reaction mixture was concentrated to remove DMF. Then water(200.0 mL) was added into the residue. The mixture was filtered and thefiltered cake was washed with water (100.0 mL×2) to give2-bromo-3-methylbenzamide (8.7 g, 87% yield) as a brown solid. LCMS m/z[M+H]⁺=214.0/216.0.

Step b:

To the reaction mixture of 2-bromo-3-methylbenzamide (8.5 g, 39.7 mmol)and TEA (8.2 mL, 59.5 mmol) in DCM (100.0 mL) was added TFAA (8.3 mL,59.5 mmol) slowly at 0° C. The reaction mixture was stirred at 0° C. for15 min. The reaction mixture was then quenched with H₂O (20.0 mL) andextracted with DCM (50.0 mL). The combined organic layers were washedwith brine (20.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (12 g column, EtOAc inpetroleum ether from 0% to 30%) to give 2-bromo-3-methylbenzonitrile(8.3 g, quant yield) as a light yellow solid. LCMS m/z[M+H]⁺=197.9/199.9.

Step c:

The mixture of 2-bromo-3-methylbenzonitrile (4.0 g, 20.4 mmol), NBS (4.3g, 24.4 mmol) and BPO (491.0 mg, 2.0 mmol) in CCl₄ (30.0 mL) was stirredat 85° C. for 12 hours under N₂ atmosphere. The reaction mixture wasfiltered and concentrated. The residue was purified by columnchromatography (petroleum ether/EtOAc=1:0-3:1) to give2-bromo-3-(bromomethyl)benzonitrile (2.3 g, 42% yield) was obtained as awhite solid.

Step d:

To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (1.9 g, 9.2mmol) in THF (20.0 mL) at −78° C. was added LDA (6.9 mL, 13.8 mmol, 2 Min THF) dropwise and stirred at −78° C. for 1 hour.2-bromo-3-(bromomethyl)benzonitrile (2.1 g, 7.7 mmol) was then addedinto the reaction and the reaction mixture was allowed stirring at −78°C. for 0.5 hour. The reaction mixture was then warmed to 20° C. Thereaction mixture was quenched with sat. NH₄Cl solution (30.0 mL), andextracted with EtOAc (50.0 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (20 g column,petroleum ether in EtOAc from 0% to 25%) to give tert-butyl4-[(2-bromo-3-cyanophenyl)methyl]-4-cyanopiperidine-1-carboxylate (1.8g, 57% yield) as a yellow oil. LCMS m/z [M+H]⁺=304.0/306.0.

Step e:

The mixture of tert-butyl4-[(2-bromo-3-cyanophenyl)methyl]-4-cyanopiperidine-1-carboxylate (1.3g, 3.3 mmol), P(t-Bu)₃.Pd-G4 (387.0 mg, 0.7 mmol) and TEA (915.0 μL, 6.6mmol) in DMF (13.5 mL) and H₂O (1.5 mL) was stirred at 130° C. for 12hours under N₂ atmosphere. The reaction mixture was quenched with water(80.0 mL), and extracted with EtOAc (100.0 mL×2). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated togive a residue. The residue was purified by flash silica gelchromatography (20 g column, EtOAc in petroleum ether from 0% to 25%) togive tert-butyl7-cyano-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(400.0 mg, 1.2 mmol, 37% yield) as a yellow oil. LCMS m/z [M+Na]⁺=349.1.

Step f:

A reaction mixture of tert-butyl7-cyano-1-oxo-1,3-dihydrospiro[indene-2,4 (400.0 mg, 1.2 mmol),(R)-2-methylpropane-2-sulfinamide (591.0 mg, 4.9 mmol), Ti(OEt)₄ (1.7 g,7.3 mmol) and 2-Me-THF (10.0 mL) was stirred at 90° C. for 12 hoursunder N₂ atmosphere. The addition of (R)-2-methylpropane-2-sulfinamide(591.0 mg, 4.9 mmol) and Ti(OEt)₄ (1.7 g, 7.3 mmol) at 90° C. wasrepeated for 2 times in 24 hours. The crude solution was used directlyin the next step.

Step g:

NaBH₄ (13.7 mg, 0.4 mmol) was added into the crude solution oftert-butyl(1Z)-7-cyano-1-{[(R)-2-methylpropane-2-sulfinyl]imino}-1,3-dihydrospiro[indene-2,4(524.0 mg, 1.2 mmol) in 2-Me-THF (10.0 mL) at 0° C. The reaction mixturewas stirred at 0° C. for 0.5 hour. Then NaBH₄ (13.7 mg, 0.4 mmol) wasadded again, and the resulting mixture was stirred at 0° C. for 0.5hour. The reaction mixture was quenched with MeOH (1.0 mL), EtOAc (80.0mL) and H₂O (50.0 mL). The reaction mixture was filtered, and thefiltered cake was washed with EtOAc (80.0 mL×2). The filtrate wasextracted with EtOAc (80.0 mL×2). The combined organic layers werewashed with brine (20.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (20 g column, EtOAc inpetroleum ether from 0% to 50%) to give tert-butyl(1S)-7-cyano-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4(250.0 mg, 48% yield) as a yellow solid. LCMS m/z [M+Na]⁺=454.2.

Step h:

To a reaction mixture of tert-butyl(1S)-7-cyano-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(200.0 mg, 0.5 mmol) in DCM (8.0 mL) was added TFA (0.8 mL). Thereaction mixture was stirred at 25° C. for 0.5 hour. Then the reactionmixture was adjusted to pH=7-8 with TEA. The mixture was concentrated togive(R)—N-[(1S)-7-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(153.0 mg, 92% yield) as a yellow oil. LCMS m/z [M+H]⁺=332.1.

1,2,3,4-tetrahydroquinolin-6-yl acetate, Intermediate BI

Step a:

To a solution of quinolin-6-ol (1.00 g, 6.88 mmol) and TEA (2.84 mL,20.6 mmol) in DCM (50.0 mL) was added acetyl chloride (1.07 g, 13.7mmol) dropwise at 0° C. The reaction mixture was stirred at 20° C. for 1hour. The reaction mixture was poured into H₂O (100.0 mL) and extractedwith DCM (50.0 mL×2). The combined organic layers were washed with brine(50.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give an orange residue. The residue was purified byflash silica gel chromatography (20 g column, ethyl acetate in petroleumether from 0% to 30%) to give the product of quinolin-6-yl acetate (1.20g, 94% yield) as a yellow oil. LCMS m/z [M+H]⁺=188.0.

Step b:

A solution of quinolin-6-yl acetate (1.20 g, 6.41 mmol) and PtO₂ (218.0mg, 961.0 umol) in THE (50.0 mL) was stirred at 20° C. for 12 hoursunder H₂ (15 psi). The reaction mixture was filtered and the filtratewas concentrated under reduced pressure to give a residue, which waspurified by flash silica gel chromatography (20 g column, ethyl acetatein petroleum ether from 0% to 20%) to give1,2,3,4-tetrahydroquinolin-6-yl acetate (1.00 g, 82% yield) as a yellowoil. LCMS m/z [M+H]⁺=192.1.

[(4-acetamidophenyl)(fluorosulfonyl)amino]sulfonyl fluoride,Intermediate BJ

Step a:

To a solution of LiN(SO₂F)₂ (2.74 g, 14.7 mmol) and PhI(OAc)₂ (3.54 g,11.0 mmol) in DCE (30.0 mL) was added N-phenylacetamide (1.00 g, 7.39mmol) in DCE (20.0 mL) dropwise under N₂ at 20° C. The reaction mixturewas stirred at 90° C. for 20 min. The reaction mixture was concentratedunder reduced pressure to give a residue, which was purified by flashsilica gel chromatography (40 g column, ethyl acetate in petroleum etherfrom 0% to 35%) to give[(4-acetamidophenyl)(fluorosulfonyl)amino]sulfonyl fluoride (1.35 g, 58%yield) as a yellow solid. LCMS m/z [M+H]⁺=314.9.

2-bromo-3-(bromomethyl)-6-methoxypyridine, Intermediate BK

Step a:

NaBH₄ (327.0 mg, 8.6 mmol) was added in portions to the mixture of2-bromo-6-methoxypyridine-3-carbaldehyde (3.75 g, 17.3 mmol, CAS#1060810-41-4) in MeOH (120 mL) at 25° C. The mixture was stirred at 25°C. for 5 min. The reaction was quenched with H₂O (150 mL). The MeOH wasremoved under reduced pressure. The combined mixture was extracted withethyl acetate (100 mL×3). The combined organic layers were washed withbrine (150 mL), dried over anhydrous Na₂SO₄, filtered and concentratedto give a residue. The residue was purified by flash silica gelchromatography (petroleum ether:ethyl acetate=100:0 to 100:20) to afford(2-bromo-6-methoxypyridin-3-yl)methanol (4.7 g, combined product) as ayellow oil. LCMS m/z [M+H]⁺=218.0/220.0.

Step b:

The compound of (2-bromo-6-methoxypyridin-3-yl)methanol (4.50 g, 20.6mmol) and CBr₄ (8.19 g, 24.7 mmol) were added in DCM (200 mL). PPh₃(6.47 g, 24.7 mmol) in DCM (50 mL) was then added dropwise at 0° C. Themixture was stirred at 0° C. for 0.5 h. The reaction was then quenchedwith brine (100 mL) and the partitioned layers were separated. Theaqueous phase was extracted with DCM (100 mL×2). The combined organiclayers were washed with brine (150 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byflash silica gel chromatography (petroleum ether:ethyl acetate=100:10)to afford 2-bromo-3-(bromomethyl)-6-methoxypyridine (5.7 g, 99% yield)as a white solid. LCMS m/z [M+H]⁺=281.8.

(R)—N-[(7S)-2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-yl]-2-methylpropane-2-sulfinamide,Intermediate BL

Step a:

The compound of tert-butyl 4-cyanopiperidine-1-carboxylate (2.43 g, 11.6mmol) was placed in THE (100 mL). The LDA (10.6 mL, 21.2 mmol, 2M inTHF) was added dropwise into the mixture at 0° C. The mixture wasstirred at 0° C. for 0.5 hour. The2-bromo-3-(bromomethyl)-6-methoxypyridine (3.0 g, 10.6 mmol,Intermediate BK) in THE (50 mL) was added dropwise into the mixture at0° C. The mixture was allowed to warm to 25° C. and stirred for 2 hours.The reaction was quenched by addition of saturated NH₄Cl (100 mL). Themixture was extracted with ethyl acetate (100 mL×2). The combinedorganic layers were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (petroleum ether:ethylacetate=100:0 to 100:20) to afford tert-butyl4-[(2-bromo-6-methoxypyridin-3-yl)methyl]-4-cyanopiperidine-1-carboxylate(2.7 g, 62% yield) as a yellow oil. LCMS m/z [M+H]⁺=410.0/412.0.

Step b:

The compound of tert-butyl4-[(2-bromo-6-methoxypyridin-3-yl)methyl]-4-cyanopiperidine-1-carboxylate(1.7 g, 4.1 mmol) was added in the 2-Me-THF (20 mL) and PhMe (20 mL).i-PrMgCl.LiCl (6.4 mL, 8.3 mmol, 1.3 M in THF) and n-BuLi (1.7 mL, 4.1mmol, 2.5 M in hexane) were added at −78° C. The reaction mixture wasstirred at −78° C. for 1 hour. The mixture was slowly warmed to 25° C.and stirred for 15 h. The reaction was quenched with saturated NH₄Cl (20mL). The mixture was adjusted to pH=5-6 with HCl (2 N). The mixture wasextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (petroleum ether:ethyl acetate=100:0 to 100:30) toafford tert-butyl2-methoxy-7-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(160 mg, 12% yield) as a white solid. LCMS m/z [M+H]⁺=333.1

Step c:

To a solution of tert-butyl2-methoxy-7-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(160 mg, 0.5 mmol) and Ti(OEt)₄ (0.5 mL, 2.4 mmol) in 2-Me-THF (10 mL)was added (R)-2-methylpropane-2-sulfinamide (116 mg, 1.0 mmol). Thereaction mixture was stirred at 90° C. for 12 h under N₂. Additional(R)-2-methylpropane-2-sulfinamide (116 mg, 1.0 mmol) and Ti(OEt)₄ (0.5mL, 2.4 mmol) were added. The reaction mixture was stirred at 90° C. foranother 12 h under N₂. The reaction was diluted with EtOAc (20 mL) andH₂O (10 mL) was added where a lot of white solid formed. The mixture wasfiltered and the filtrate was extracted with ethyl acetate (10 mL×3).The combined organic layers were washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by prep-TLC (ethyl acetate/petroleum ether=1/1) toafford tert-butyl(7Z)-2-methoxy-7-{[(R)-2-methylpropane-2-sulfinyl]imino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(70.0 mg, 33% yield) as a yellow oil. LCMS m/z [M+H]⁺=436.1.

Step d:

The compound of tert-butyl(7Z)-2-methoxy-7-{[(R)-2-methylpropane-2-sulfinyl]imino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(70 mg, 160 μmol) in THF (2 mL) was added NaBH₄ (18 mg, 480 μmol) at 0°C. The mixture was stirred at 25° C. for 1 h. The reaction mixture wasquenched with MeOH. The solution was added into H₂O (10 mL) and EtOAc(10 mL). The mixture was filtered and extracted with EtOAc (10 mL×2).The combined organic layers were washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by prep-TLC (ethyl acetate:petroleum ether=1:1) toafford tert-butyl(7S)-2-methoxy-7-{[(R)-2-methylpropane-2-sulfinyl]amino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(70 mg, quant. crude yield) as a colorless oil. LCMS m/z [M+H]⁺=438.1.

Step e:

tert-butyl(7S)-2-methoxy-7-{[(R)-2-methylpropane-2-sulfinyl]amino}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate(70 mg, 0.2 mmol) was added in the solution of TFA (0.2 mL) and DCM (2mL). The mixture was stirred at 25° C. for 0.5 h. The mixture wasadjusted to pH=8-9 with TEA. The mixture was concentrated to give(R)—N-[(7S)-2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-yl]-2-methylpropane-2-sulfinamide(60 mg, crude product) as a colorless oil. LCMS m/z [M+H]⁺=338.1.

3-bromo-2-(bromomethyl)-6-methoxypyridine, Intermediate BM

Step a:

A mixture of 3-bromo-6-chloropyridine-2-carboxylic acid (10.0 g, 42.2mmol, CAS #929000-66-8) in MeOH (100.0 mL)/SOCl₂ (10.0 mL) was stirredat 80° C. for 3 hours. The reaction mixture was concentrated in vacuo togive methyl 3-bromo-6-chloropyridine-2-carboxylate (10.4 g, 99% yield)as a yellow solid.

Step b:

To the solution of methyl 3-bromo-6-chloropyridine-2-carboxylate (5.0 g,19.9 mmol) and MeOH (1.0 mL, 25.8 mmol) in THE (15.0 mL, freshly driedover NaH) was added t-BuOK (29.8 mL, 29.8 mmol, 1 M in THF) slowly over20 min at 0° C. under N₂ atmosphere. The reaction mixture was stirred at0° C. for 5 min. The reaction mixture was quenched with ice-cold sat.NH₄Cl solution (30.0 mL), and extracted with EtOAc (50.0 mL×2) rapidly.The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by flash silica gelchromatography (40 g column, EtOAc in petroleum ether from 0%˜10%) togive methyl-3-bromo-6-methoxypyridine-2-carboxylate (4.5 g, 92.0% yield)as a colorless oil.

Step c:

To the mixture of methyl-3-bromo-6-methoxypyridine-2-carboxylate (9.0 g,36.5 mmol) in MeOH (30 mL) was added NaBH₄ (1.38 g, 36.5 mmol). Themixture was stirred at 25° C. for 0.5 hour. The addition of NaBH₄ (1.38g, 36.5 mmol) at 25° C. was repeated for 2 times each 0.5 hour. Thereaction mixture was concentrated. The residue was purified by flashsilica gel chromatography (40 g column, EtOAc in petroleum ether from 0%to 15%) to give (3-bromo-6-methoxypyridin-2-yl)methanol (6.40 g, 81%yield) as a colorless oil. LCMS m/z [M+H]⁺=217.7/219.7.

Step d:

(3-bromo-6-methoxypyridin-2-yl)methanol (2.5 g, 11.4 mmol) and CBr₄ (4.5g, 13.6 mmol) were added into DCM (30 mL). PPh₃ (3.6 g, 13.6 mmol) inDCM (10 mL) was added dropwise into the reaction mixture at 0° C. Themixture was stirred at 0° C. for 0.5 hour. The reaction was concentratedto give a residue. The residue was purified by flash silica gelchromatography (40 g column, EtOAc in petroleum ether from 0% to 10%) toafford 3-bromo-2-(bromomethyl)-6-methoxypyridine (2.69 g, 84% yield) asa colorless oil. LCMS m/z [M+H]⁺=281.8.

(R)—N-[(5S)-2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl]-2-methylpropane-2-sulfinamide,Intermediate BN

(R)—N-[(5S)-2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl]-2-methylpropane-2-sulfinamidewas synthesized as described for Intermediate BL, coupling tert-butyl4-cyanopiperidine-1-carboxylate with3-bromo-2-(bromomethyl)-6-methoxypyridine (Intermediate BM) in Step a.In Step b, the conditions P(t-Bu)₃-Pd-G4 and TEA in DMF and H₂O at 130°C. for 12 hours were used for the cyclization. LCMS of finalIntermediate BN: LCMS m/z [M+H]⁺=338.1.

3-(bromomethyl)-4-iodobenzonitrile, Intermediate BO

Step a:

4-Iodo-3-methylbenzonitrile (2.00 g, 8.20 mmol), BPO (199.0 mg, 822.0μmol) and NBS (2.20 g, 12.30 mmol) were added in DCE (30.0 mL), and thereaction mixture was evacuated and refilled for 3 times with N₂ andstirred at 80° C. for 2 hours. Another batch of NBS (1.50 g, 8.44 mmol)was added and the mixture was stirred at 80° C. for another 12 hours.The reaction mixture was concentrated under reduced pressure andpurified by flash silica gel chromatography (petroleum ether:EtOAc=100:0to 100:5) to afford 3-(bromomethyl)-4-iodobenzonitrile (1.60 g, 61%yield) as a white solid. ¹HNMR (400 MHz, CDCl₃) 8.03-8.00 (m, 1H),7.77-7.72 (m, 1H), 7.28-7.24 (m, 1H), 4.58 (s, 2H).

(R)—N-[(1S)-5-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide,Intermediate BP

(R)—N-[(1S)-5-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamidewas synthesized as described via Steps d-h of Intermediate BH, startingwith tert-butyl 4-cyanopiperidine-1-carboxylate and3-(bromomethyl)-4-iodobenzonitrile (Intermediate BO) in Step a.Characterization of the final product: LCMS m/z [M]⁺=331.9.

tert-butyl (4,5,6-trichloropyridin-2-yl)carbamate, Intermediate BO

Step a:

A mixture of 6-chloropyridin-2-amine (2.5 g, 19.4 mmol) and NCS (2.8 g,21.3 mmol) in MeCN (40 mL) was stirred at 80° C. for 18 hours. Thereaction mixture was concentrated in vacuo to give a residue, which waspurified by silica gel chromatography (ethyl acetate in petroleumether=0% to 30%) to afford 5,6-dichloropyridin-2-amine (2.1 g, 66%yield) as a white solid. LCMS m/z [M+H]⁺=162.8.

Step b:

To a solution of 5,6-dichloropyridin-2-amine (2.1 g, 12.8 mmol) inanhydrous THE (20 mL) was added NaHMDS (25.6 mL, 25.6 mmol) at 0° C. Thereaction mixture was stirred at this temperature for 30 mins, then thesolution of (Boc)₂O (2.9 g, 13.4 mmol) in anhydrous THF (10 mL) wasadded. The resulting mixture was stirred at 0° C. for 1.5 hours. Themixture was quenched with saturated NH₄Cl and extracted with ethylacetate (50 mL×2). The organic phases were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue, which was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 10%) to afford tert-butyl(5,6-dichloropyridin-2-yl)carbamate (2.5 g, 74% yield) as a colorlessoil.

Step c:

To a mixture of tert-butyl (5,6-dichloropyridin-2-yl)carbamate (1.2 g,4.6 mmol) in anhydrous THF (15 mL) at −70° C. was added LDA (5.7 mL,11.4 mmol) under N₂ atmosphere. After stirring at this temperature for 2hours, NCS (1.1 g, 8.2 mmol) in THE (5 mL) was added. The resultingmixture was stirred at −70° C. for 2 hours and 10 hours at 20° C. Thereaction mixture was diluted with H₂O (40 mL) and extracted with ethylacetate (45 mL×2). The combined organic phases were washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give a residue, which was purified by silica gel chromatography(ethyl acetate in petroleum ether=0% to 5%) to afford tert-butyl(4,5,6-trichloropyridin-2-yl)carbamate (1.3 g, purity: 30%) as acolorless oil.

(R)-2-methyl-N-[(3S)-1′-[5-(sodiosulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]propane-2-sulfinamide,Intermediate BR

Step a:

A mixture of(R)—N-[(3S′)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(450 mg, 1.5 mmol, synthesized via Step a of Example 120),2,5-dibromopyrazine (416 mg, 1.8 mmol) and TEA (1.0 mL, 7.3 mmol) in DMF(10 mL) was stirred at 80° C. for 2 hours. The reaction mixture was thendiluted with ethyl acetate (30 mL), and washed with H₂O (20 mL×2). Theorganic phase was washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 70%) to afford(R)—N-[(3S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(580 mg, 86% yield) as a brown solid. LCMS m/z [M+H]⁺=463.0/465.0.

Step b:

A mixture of(R)—N-[(3S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(550 mg, 1.2 mmol), 2-ethylhexyl 3-mercaptopropanoate (307 mg, 1.4mmol), Pd₂(dba)₃ (108 mg, 118 μmol), XantPhos (136 mg, 236 μmol) and TEA(0.5 mL, 3.5 mmol) in toluene (30 mL) was stirred at 100° C. for 12hours under N₂ atmosphere. The reaction mixture was concentrated invacuo to give a residue, which was purified by silica gel chromatography(ethyl acetate in petroleum ether=0% to 55%) to afford 2-ethylhexyl3-((5-((S)-1-((R)-1,1-dimethylethylsulfinamido)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(650 mg, 92% yield) as a yellow oil. LCMS m/z [M+H]⁺=601.6.

Step c:

To a mixture of 2-ethylhexyl3-((5-((S)-1-((R)-1,1-dimethylethylsulfinamido)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(650 mg, 1.1 mmol) in anhydrous THE (3.0 mL) was added MeONa (116 mg,2.2 mmol), the resulting mixture was stirred at 20° C. for 12 hoursunder N₂ atmosphere. The reaction mixture was then concentrated in vacuoto give the crude product, which triturated with petroleum ether:ethylacetate=10:1 (15 mL) and filtered. The solid was collected and dried invacuo to afford(R)-2-methyl-N-[(3S)-1′-[5-(sodiosulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]propane-2-sulfinamide(650 mg, purity: 70%) as a yellow solid. LCMS m/z [M+H −Na]⁺=417.0.

2-bromo-5-((2,3-dichloropyridin-4-yl)oxy)pyrazine, Intermediate BS

Step a:

A mixture of 2,5-dibromopyrazine (287 mg, 1.2 mmol),2,3-dichloropyridin-4-ol (300 mg, 1.8 mmol) and Cs₂CO₃ (593 mg, 1.8mmol) in DMF (5.0 mL) was stirred at 85° C. for 24 hours. The reactionmixture was concentrated under reduced pressure. The residue was dilutedwith water (30.0 mL) and extracted ethyl acetate (50.0 mL×2). Thecombined organic layers were washed with H₂O (30.0 mL) and brine (30.0mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (petroleum ether:ethyl acetate=100:0 to 100:15) to give2-bromo-5-((2,3-dichloropyridin-4-yl)oxy)pyrazine (530 mg) as a lightyellow oil. LCMS m/z [M+H]⁺=321.8.

tert-butyl7-bromo-3-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate,Intermediate BT

Step a:

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate(10.0 g, 41.1 mmol) in THE (150.0 mL) was added LDA (24.6 mL, 49.3 mmol,2 M) at −78° C. under N₂. The mixture was stirred at −78° C. for 1 hour.Then the solution of 1-bromo-2-(bromomethyl)benzene (12.3 g, 49.3 mmol)in THE (50.0 mL) was added at −78° C. The mixture was stirred at 20° C.for 11 hours under N₂. The mixture was poured into H₂O (300.0 mL) andextracted with EtOAc (300.0 mL×2). The combined organic phases werewashed with brine (300.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give 1-(tert-butyl) 4-methyl4-(2-bromobenzyl)piperidine-1,4-dicarboxylate (20 g, 50% purity) as ayellow oil.

Step b:

A solution of 1-tert-butyl 4-methyl4-[(2-bromophenyl)methyl]piperidine-1,4-dicarboxylate (20.0 g, 50%purity) and KOH (13.5 g, 242.0 mmol) in MeOH/H₂O (50.0 mL/50.0 mL) wasstirred at 60° C. for 12 hours. The mixture was concentrated underreduced pressure to about 50.0 mL. The residue was diluted with H₂O(300.0 mL), extracted with EtOAc/Petroleum ether (1/10, 220.0 mL). Theorganic phase was discarded. The aqueous phase was acidified with 6 NHCl to pH=5-6, then extracted with EtOAc (250.0 mL×2). The combinedorganic phase were washed by brine (100.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give4-[(2-bromophenyl)methyl]-1-[(tert-butoxy)carbonyl]piperidine-4-carboxylicacid (5.98 g, 15.0 mmol) as a white solid. LCMS m/z [M+H]⁺=298.0.

Step c:

To a solution of4-[(2-bromophenyl)methyl]-1-[(tert-butoxy)carbonyl]piperidine-4-carboxylicacid (6.2 g, 14.7 mmol) in DCM (100.0 mL) was added SOCl₂ (2.1 mL, 29.4mmol) at 20° C. under N₂. The mixture was stirred at 20° C. for 1 hour.White suspension was observed, then AlCl₃ (2.9 g, 22.0 mmol) was addedin portions at 0° C. The mixture was stirred at 20° C. for 2 hours underN₂. The mixture was adjusted to pH=9 with 2N NaOH. To the mixture wasadded (Boc)₂O (7.6 mL, 33.5 mmol) and stirred at 20° C. for 12 hours.The mixture was extracted with DCM (100.0 mL×2). The combined organicphases were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether=0˜10%) toafford tert-butyl7-bromo-3-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.6 g, 4.2 mmol) as a yellow solid.

Step d:

To a solution of tert-butyl7-bromo-3-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1-carboxylate(1.1 g, 2.9 mmol) in EtOH (20.0 mL) were added NH₄OAc (8.9 g, 115.0mmol) and NaBH₃CN (907.0 mg, 14.4 mmol) in portions (4 times). Themixture was stirred at 80° C. for 12 hours. The mixture was concentratedunder reduced pressure to give a residue. The residue was extracted withEtOAc (100.0 mL×2), and the combined organic phases were washed with 2Naqueous NaOH (50.0 mL×2). The separated organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive tert-butyl1-amino-4-bromo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.1 g, quant. crude yield). LCMS m/z [M+H]⁺=381.0/383.0.

1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile,Intermediate BU

Step a:

To a solution of tert-butyl3-amino-7-bromo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.1 g, Intermediate BT) in DCM (10.0 mL) were added (Boc)₂O (1.3 g, 5.8mmol) and Et₃N (1.2 mL, 8.6 mmol). The mixture was stirred at 20° C. for1 hour. The reaction mixture was concentrated under reduced pressure andpurified by flash silica gel chromatography (ethyl acetate in petroleumether=0˜10%) to afford tert-butyl7-bromo-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(840.0 mg, 1.7 mmol) as a white solid. LCMS m/z [M+H]⁺=481.1/483.1.

Step b:

To a solution of tert-butyl7-bromo-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(600.0 mg, 1.2 mmol) in DMF (20.0 mL) were added Zn(CN)₂ (1.2 g, 9.9mmol) and XantPhos-Pd-G4 (119.0 mg, 124.0 μmol). The mixture was stirredat 100° C. for 12 hours under N₂. The combined mixture was filtered,extracted with EtOAc (50.0 mL×3) and washed with brine (50.0 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byflash silica gel chromatography (ethyl acetate in petroleum ether=0˜15%)to afford tert-butyl3-{[(tert-butoxy)carbonyl]amino}-7-cyano-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(500.0 mg, 67% yield) as a white solid. LCMS m/z [M+Na]⁺=450.1.

Step c:

To a solution of tert-butyl3-{[(tert-butoxy)carbonyl]amino}-7-cyano-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(250.0 mg, 584.0 μmol) in MeOH (5.0 mL) was added HCl/MeOH (5.0 mL, 4M),and the mixture was stirred at 20° C. for 12 hours. The mixture wasconcentrated under reduced pressure to give1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitriledihydrochloride (150 mg, 86% crude yield) as a white solid. LCMS m/z[M+H]⁺=228.1.

tert-butylN-[(tert-butoxy)carbonyl]-N-(1′-{3-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate,Intermediate BV

6-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-3-olwas synthesized as described for Intermediate BE above, coupling methyl3,5-dichloropyrazine-2-carboxylate and1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine (Intermediate E) in Stepa.6-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-3-ol(300 mg, 657 μmol) was then protected in Step c under the followingconditions: Boc₂O (285 mg, 1.31 mmol) and TEA (250 μL, 1.97 mmol) in DCM(5 mL) was stirred at 20° C. for 5 hours. The mixture was concentratedunder reduced pressure to afford tert-butylN-[(tert-butoxy)carbonyl]-N-(1′-{3-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(500 mg, 80% purity, 93% yield) as a yellow oil. LCMS m/z [M+H]⁺=657.2.

6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one, Intermediate BW

Step a:

1,6-naphthyridine (0.965 g, 7.41 mmol) was dissolved in MeOH (8.5 mL)and charged with iodomethane (921 μL, 14.8 mmol). The vial was sealedand heated to 65° C. and stirred for 16 hrs. The solvent was removed,the residue taken up in a small amount of MeOH (1-2 mL) and ethylaacetate was charged. The mixture was filtered, washed with EA and airdried to constant weight to afford 6-methyl-1,6-naphthyridin-6-iumiodide (1.56 g).

Step b:

6-methyl-1,6-naphthyridin-6-ium iodide (1.56 g, 5.73 mmol) was suspendedin water (10 mL) and cooled to 0° C. The reaction was charged with NaOH(1.25 g, 31.5 mmol) in water (10 mL) and tripotassiumhexakis(iminomethanide) iron (4.04 g, 12.3 mmol) in water (10 mL). Thesolution was stirred for 1 hr at 0° C. then overnight at rt. The mixturewas extracted with CHCl₃, dried and concentrated. The residue waspurified by flash silica gel chromatography (eluting with MeOH:DCM=0:100to 10:90) to afford 6-methyl-5,6-dihydro-1,6-naphthyridin-5-one (540 mg)as a light yellow solid. LCMS: [M+H]⁺=161.

Step c:

6-methyl-5,6-dihydro-1,6-naphthyridin-5-one (109 mg, 0.6805 mmol) wasdissolved in MeOH (10 mL). The solution was pumped a 10% Pd/C cartridgeat 1 mL/min under 70 bars of H₂ at 70° C. for 90 min. Solvent wasremoved to afford 6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one(90 mg) as a white solid. LCMS m/z [M+H]⁺=165.

(S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate BX

(S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine wassynthesized as described for Intermediate T, using2-(bromomethyl)-4-fluoro-1-iodobenzene for the coupling in Step a.Characterization of the final intermediate: H NMR (400 MHz, DMSO-d6) δppm 8.94 (br s, 2H) 8.58 (br s, 3H) 7.61 (br dd, J=7.81, 5.86 Hz, 1H)7.07-7.18 (m, 2H) 4.37 (br d, J=4.39 Hz, 1H) 3.71 (s, 1H) 3.31 (br d,J=13.43 Hz, 1H) 3.13-3.22 (m, 2H) 2.87-3.10 (m, 3H) 1.95-2.11 (m, 1H)1.64-1.85 (m, 2H) 1.50 (br d, J=14.40 Hz, 1H) 1.09 (s, 4H).

tert-butyl((1S)-5-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate BY

tert-butyl((1S)-5-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamatewas synthesized as described for Intermediate J, coupling6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (IntermediateA) with (S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(Intermediate BX). Characterization of final intermediate BY: LCMS m/z[M+H]⁺=649.2.

(R)-7-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine, IntermediateBZ

Step a:

To a mixture of 2,3-difluorobenzaldehyde (10 g, 70.3 mmol) andN,N-dimethylpyridin-4-amine (103 mg, 0.8436 mmol) in ACN (100 mL) wasadded trimethylsilanecarbonitrile (7.87 g, 79.4 mmol), where a cold bathwas used to offset the small exotherm during addition. The reaction wasstirred at rt for 5 h. The reaction was concentrated to give2-(2,3-difluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile as a yellowoil.

Step b:

2-(2,3-difluorophenyl)-2-[(trimethylsilyl)oxy]acetonitrile (8.45 g, 35.0mmol) in THF (65 mL) was cooled to −78° C. and charged with 1M LHMDS(38.5 mL, 38.5 mmol) not allowing the temperature to rise above −65° C.during the addition. The reaction mixture was stirred at −78° C. for 1.5h, then tert-butyl 4-oxopiperidine-1-carboxylate (7.67 g, 38.5 mmol) inTHF (10 mL) was added, again not allowing the temperature to rise above−65° C. during the addition, and the reaction was stirred at −78° C. for3 h. Hydrogen chloride (84.0 mL, 84.0 mmol) was then added to thereaction mixture and the solution was allowed to warm to rt and stirred16 h. The organic layer was separated and the aqueous layer was backextracted with EA. The organic layer was dried, concentrated andpurified by column chromatography (330 g column, 0-40% EA/hep) to givetert-butyl4-(cyano(2,3-difluorophenyl)(hydroxy)methyl)-4-hydroxypiperidine-1-carboxylate(4.5 g) as a colorless oil and tert-butyl4-(2,3-difluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (4.3 g) as awhite solid. LCMS m/z [M+H−100]⁺=241.9.

Step c:

Tert-butyl 4-(2,3-difluorobenzoyl)-4-hydroxypiperidine-1-carboxylate(2.25 g, 6.59 mmol) and (tert-butoxy)potassium (7.24 mL, 7.24 mmol) weredissolved in THE (3 mL) and heated in a microwave at 70° C. for 1 hr.Water was then added and the mixture was extracted with EA. The combinedorganic layer was dried and concentrated to afford tert-butyl7-fluoro-3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate as alight yellow oil. LCMS m/z [M+H−100]⁺=222.2.

Step d:

To a mixture of tert-butyl7-fluoro-3-oxo-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-carboxylate(4.2 g, 13.0 mmol) and (R)-2-methylpropane-2-sulfinamide (2.36 g, 19.5mmol) in 2-MeTHF (5 mL) was added tetratitanium-1-ylium tetraethanolate(17.7 mL, 52.0 mmol). The vial was then sealed and heated to 95° C. for16 h. The reaction mixture was then cooled and was diluted with 2-MeTHF(20 mL) and further cooled to −10° C. To the solution was then addedboranium lithiumuide (283 mg, 13.0 mmol) and the reaction mixture wasstirred for 20 min. Ethyl acetate was then added to the reaction mixtureand stirred for 10 min. The reaction mixture was then added dropwise toa vigorously stirred brine solution. The resulting suspension wasstirred for 15 min, charged with celite, then filtered. The layers wereseparated and the organic layer was pre-absorbed on SiO₂ (8 g). Themixture was purified by column chromatography (25 g column, 25-75EA/hep)to afford tert-butyl(R)-3-(((R)-tert-butylsulfinyl)amino)-7-fluoro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate(1.6 g, 29% yield) as a white foam. ¹HNMR (400 MHz, Methanol-d₄) δ 7.44(d, J=7.6 Hz, 1H), 7.30-7.26 (m, 1H), 7.13-7.08 (m, 1H), 4.92 (s, 1H),3.67-3.62 (m, 1H), 3.50-3.36 (m, 3H), 2.59-2.47 (m, 1H), 2.31-2.10 (m,3H).

Step e:

tert-butyl(3R)-7-fluoro-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-carboxylate(1.54 g, 3.61 mmol) in MeOH (25 mL) was charged with hydrogen chloride(9.02 mL, 36.1 mmol) and the reaction mixture was stirred at rt for 5 h.The solvent was then removed and chased with MTBE to yield(R)-7-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine dihydrochlorideas a white solid. LCMS m/z [M+H]⁺=649.2.

tert-butyl((3R)-7-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamate,Intermediate CA

tert-butyl((3R)-7-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamatewas synthesized as described for Intermediate J, coupling6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (IntermediateA) with (3R)-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminedihydrochloride (Intermediate BZ). LCMS m/z [M+H]⁺=651.2.

(R)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine, Intermediate CB

Step a:

A mixture of tert-butyl3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (200 mg, 659μmol, synthesized via Steps a-d of Intermediate AP), Ti(OEt)₄ (599 mg,2.63 mmol) and (R)-2-methylpropane-2-sulfinamide (119 mg, 988 umol) in2-Me-THF (10 mL) was stirred at 80° C. for 12 hours under N₂ atmosphere.The reaction mixture was then concentrated to give tert-butyl(R,Z)-3-((tert-butylsulfinyl)imino)-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate(600 mg, quant. crude yield). LCMS m/z [M+Na]=429.0.

Step b:

To a mixture of tert-butyl(3Z)-3-{[(R)-2-methylpropane-2-sulfinyl]imino}-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-carboxylate(5.5 g, crude) in THE (50 mL) was added borane lithium hydride (331 mg,15.1 mmol) at 0° C., then the resulting mixture was stirred at 25° C.for 2 hours. The reaction mixture was quenched with sat.NH₄Cl, dilutedwith H₂O (200 mL), then extracted with ethyl acetate (200 mL×2). Theorganic phases were washed with brine (200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel column (elution: petroleumether:ethyl acetate=1:0-1:3) to give tert-butyl(3R)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-carboxylate(4.1 g, 74% yield) as a white solid. LCMS m/z [M+Na]⁺=431.0.

Step c:

Dissolved tert-butyl(3R)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-carboxylate(1.15 g, 2.81 mmol) in 20 mL MeOH then added hydrogen chloride (7.00 mL,28.0 mmol). The reaction mixture was stirred at 60° C. for 30 min. Thereaction mixture was then concentrated to an oil. MTBE was added and theproduct precipitated. The mixture was filtered and the solid was washedwith MTBE and dried to give(3R)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine dihydrochloride (750mg, 96% yield).

Tert-butyl((3R)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamate,Intermediate CC

Tert-butyl((3R)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamatewas synthesized as described for Intermediate J, coupling6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (IntermediateA) with (R)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine dihydrochloride(Intermediate CB). LCMS m/z [M+H−100]⁺=533.3.

(R)—N-[(1S)-4,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide,Intermediate CD

(R)—N-[(1S)-4,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamidewas synthesized as described for Intermediate AL, coupling 1-tert-butyl4-methyl piperidine-1,4-dicarboxylate and1-(bromomethyl)-2,4-difluorobenzene in Step a. tert-butyl(1S)-4,6-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylatewas then deprotected as follows: the mixture of tert-butyl(1S)-4,6-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(190 mg, 429 μmol) in DCM (5 mL) and TFA (1 mL) was stirred at 20° C.for 2 hours. The mixture was concentrated under reduced pressure and theresidue was diluted with MeOH. The mixture was adjusted with Na₂CO₃ topH=8. The mixture was filtered and the filtrate was concentrated underreduced pressure to afford(R)—N-[(1S)-4,6-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(140 mg, 96% yield) as a yellow oil. LCMS m/z [M+H]⁺=343.0.

(5-chloropyrazin-2-yl)(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)methanone,Intermediate CE

Step a:

A resealable reaction vial was charged with5-chloropyrazine-2-carboxylic acid (500 mg, 3.15 mmol) and sulfurooyldichloride (5.73 mL, 78.7 mmol). The mixture was charged with DMF (3drops) and heated to 80° C. for 3.5 h. The solvent was removed in vacuoand chased with toluene to give a yellow crystalline solid. The solidwas suspended in DCM (4 mL), cooled to 0-5° C. and charged withtriethylamine (1.74 mL, 12.6 mmol) and1,2,3,4-tetrahydro-1,5-naphthyridine (422 mg, 3.15 mmol) and thereaction mixture was stirred for 1 h. The reaction mixture was thencharged with bicarbonate, and extracted with DCM. The organic layer wasdried, concentrated and purified by column chromatography (Si-25 gcolumn, 70-100% EA/hep) to afford(5-chloropyrazin-2-yl)(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)methanone(748 mg, 86% yield). LCMS m/z [M+H]⁺=275.1.

tert-butyl(S)-(1′-(5-amino-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate CF

Step a:

A disposable tube was charged with(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (203 mg, 0.738 mmol,Intermediate I) triethylamine (148 mg, 1.47 mmol),5-chloro-1,3,4-thiadiazol-2-amine (100 mg, 0.738 mmol, CAS #37566-40-8)and a stir bar. DMF (2 mL) was added and the solution was stirred at 80°C. for 2 hr where the intermediate(S)-5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1,3,4-thiadiazol-2-aminewas formed. The reaction mixture was then partitioned between EtOAc andwater. The layers were separated, and the aqueous layer was concentratedand dried under high vacuum. The residue was then resuspended in DCM (2mL) and triethylamine (200 uL) and di-tert-butyl dicarbonate (186 μL,0.8113 mmol) were added. The reaction mixture was stirred at rt for 2hr. The mixture was concentrated in vacuo then purified by columnchromatography (0-10% MeOH in DCM w/ 1% NH4OH) to give tert-butylN-[(3S)-1′-(5-amino-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(101 mg, 34% yield). LCMS m/z [M+H]⁺=402.6.

tert-butylN-[(3S)-1′-(5-bromo-1,3-thiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate CG

Step a:

A mixture of 2,5-dibromo-1,3-thiazole (106 mg, 0.436 mmol),(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine dihydrochloride (120mg, 0.436 mmol, Intermediate I) and triethylamine (121 μL, 0.873 mmol)in 2 mL DMF was heated at 100° C. for 20 hr. The reaction mixture wascooled to rt and di-tert-butyl dicarbonate (109 μL, 0.480 mmol) wasadded and the mixture was stirred at rt for 48 hr. The reaction mixturewas then partitioned between EtOAc and water. The aqueous layer wasextracted 3× with EtOAc. The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (0-100% ethyl acetate in heptanes) to givetert-butylN-[(3S)-1′-(5-bromo-1,3-thiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(47.0 mg, 23% yield). LCMS m/z [M+H]⁺=464.5/466.5.

(S)-1′-(5-chloropyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate CH

Step a:

Dissolved 2,5-dichloropyrazine (50 mg, 0.336 mmol), dicaesium(1+)carbonate (436 mg, 1.34 mmol), and(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(92.3 mg, 0.336 mmol, Intermediate I) in DMF (2 mL). The reactionmixture was stirred at 80° C. for 3 h. The reaction mixture was thenpartitioned between EtOAc and water, and the aqueous layer was extracted3× with EtOAc. The organic layers were combined, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (0-10% MeOH in DCM w/ 1% NH₄OH) to give(3S)-1′-(5-chloropyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(52.0 mg, 49% yield). LCMS m/z [M+H]⁺=315.4.

(S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate CI

Step a:

2,5-dibromopyrazine (1.23 g, 5.19 mmol),(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine dihydrochloride (1.3g, 4.72 mmol, Intermediate I) and TEA (3.26 mL, 23.6 mmol) were added inDMF (20 mL). The reaction mixture was stirred at 85° C. for 12 hr. Themixture was then diluted with ethyl acetate (100 mL), the organic layerseparated and washed with H₂O (20 mL×3), brine (30 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (DCM:MeOH=100:0to 100:5) to afford(S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(1.2 g, 71% yield) as a yellow oil. LCMS m/z [M+H]⁺=360.0/362.0.

tert-butylN-{4-[(5-bromopyrimidin-2-yl)sulfanyl]-3-chloropyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate,Intermediate CJ

Step a:

The mixture of 5-bromo-2-chloropyrimidine (550 mg, 2.84 mmol),3-chloro-4-(sodiosulfanyl)pyridin-2-amine (491 mg, 2.69 mmol,Intermediate AC) and Cs₂CO₃ (1.85 g, 5.68 mmol) in DMF (5 mL) wasstirred at 80° C. for 1 hour. The mixture was diluted with H₂O (20 mL),then extracted with EtOAc (20 mL×2). The organic layer was washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=1:0˜3:1) to afford4-[(5-bromopyrimidin-2-yl)sulfanyl]-3-chloropyridin-2-amine (530 mg, 59%yield) as a yellow solid. LCMS m/z [M+H]⁺=318.8.

Step b:

The mixture of4-[(5-bromopyrimidin-2-yl)sulfanyl]-3-chloropyridin-2-amine (200 mg, 629μmol), Boc₂O (164 mg, 754 μmol) and DMAP (115 mg, 943 μmol) in DCM (10mL) was stirred at 25° C. for 12 hours. The mixture was concentratedunder reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=1:0˜10:1) to affordtert-butylN-{4-[(5-bromopyrimidin-2-yl)sulfanyl]-3-chloropyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate(300 mg, 92% yield) as a yellow solid. LCMS m/z [M+H]⁺=518.9; ¹HNMR (400MHz, DMSO-d₆): δ 8.87 (s, 2H), 8.51-8.49 (d, J=5.2 Hz, 1H), 7.94-7.92(d, J=5.2 Hz, 1H), 1.36 (s, 18H).

(R)—N-[(3S)-1′-(5-bromopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide,Intermediate CK

Step a:

The mixture of(R)—N—((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(200 mg, 652 μmol, synthesized via Step a of Example 120),5-bromo-2-chloropyrimidine (126 mg, 652 μmol), XantPhos-Pd-G4 (62.7 mg,65.2 μmol) and Cs₂CO₃ (423 mg, 1.30 mmol) in DMF (10 mL) was stirred at80° C. for 10 hours under N₂ atmosphere. The mixture was diluted withH₂O (20 mL), then extracted with EtOAc (20 mL×2). The combined organiclayer was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (petroleum ether/ethylacetate=1:0˜3:1) to afford(R)—N-[(3S)-1′-(5-bromopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(140 mg, 46% yield) as a white solid. LCMS m/z [M+H]⁺=465.0.

tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate,Intermediate CL

Step a:

A mixture of (3R)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride (100 mg, 0.4 mmol, Intermediate CB), 2,5-dibromopyrazine(108 mg, 0.5 mmol) and TEA (230 μL, 1.7 mmol) in DMF (2.0 mL) wasstirred at 85° C. for 12 hours. This reaction mixture was used for thenext step directly. LCMS m/z [M+H]⁺=361.9.

Step b:

To the reaction mixture was added (Boc)₂O (134 mg, 0.6 mmol). Thereaction mixture was stirred at 70° C. for 2 hours. The reaction mixturewas concentrated under reduced pressure to give the residue which waspurified by column chromatography (petroleum ether:ethyl acetate=100:0to 100:100, ethyl acetate:methanol=100:0 to 100:10) to give tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(110 mg, 58% yield) as a white solid. LCMS m/z [M+H]⁺=460.9.

2-chloro-N-methylpyridin-4-amine (Intermediate CM)

Step a:

A mixture of 2,4-dichloropyridine (1.00 g, 6.75 mmol) and aq. MeNH₂(30.0mL) in MeOH (10.0 mL) was stirred in sealed tube at 85° C. for 12 hours.The reaction mixture was poured into H₂O (100.0 mL) and extracted withEtOAc (100.0 mL×2). The combined organic layers were washed with brine(200.0 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (20 g, ethyl acetate inpetroleum ether from 0% to 30%) to give 2-chloro-N-methylpyridin-4-amine(600.0 mg, 62% yield) as a white solid. LCMS m/z [M+H]⁺=143.0; ¹HNMR(400 MHz, CD₃OD): 7.78-7.80 (m, 1H), 6.47-6.52 (m, 2H), 2.80-2.83 (m,3H).

(1′S)-1′,3′-dihydrospiro[azetidine-3,2′-inden]-1′-amine, IntermediateCN, and (1′R)-1′,3′-dihydrospiro[azetidine-3,2′-inden]-1′-amine,Intermediate CO

Step a:

To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (3.60 g,19.70 mmol, CAS #142253-54-1) in THE (40 mL) was added LDA (11.8 mL,23.60 mmol, 2.0 M) dropwise at −78° C. under N₂. The mixture was stirredat 0° C. for 15 min. Then to the mixture was added1-bromo-2-(bromomethyl)benzene (5.40 g, 21.60 mmol) in THE (20 mL) at−78° C. The mixture was stirred at 0-25° C. for 12 hours under N₂. Thereaction mixture was then quenched by H₂O (150 mL) and extracted withEtOAc (150 mL×2). The combined organic layers were washed with brine(150 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether=0˜10%) toafford tert-butyl3-[(2-bromophenyl)methyl]-3-cyanoazetidine-1-carboxylate (1.00 g, 14%yield) as a light yellow oil. ¹HNMR (400 MHz, CDCl₃): δ 7.10-7.57 (m,4H), 4.20 (d, J=8.8 Hz, 2H), 4.03 (d, J=8.8 Hz, 2H), 3.34 (s, 2H), 1.37(s, 9H).

Step b:

A mixture of tert-butyl3-[(2-bromophenyl)methyl]-3-cyanoazetidine-1-carboxylate (800.0 mg, 2.27mmol), PdCl₂(Amphos) (160.0 mg, 227.0 μmol, CAS #887919-35-9) and TEA(918.0 mg, 9.08 mmol) in DMA/H₂O (10 mL, 10/1) was stirred at 120° C.under N₂ for 12 hours. The reaction mixture was then poured into EtOAc(50 mL) and washed with water (30 mL×3). The organic layer was driedover anhydrous Na₂SO₄, filtered, concentrated and purified by silica gelchromatography (ethyl acetate in petroleum ether=0˜20%) to affordtert-butyl1′-oxo-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate (520.0mg, 84% yield) as a yellow solid. ¹HNMR (400 MHz, CDCl₃): δ 7.40-7.83(m, 4H), 4.26 (d, J=8.4 Hz, 2H), 3.90 (d, J=8.4 Hz, 2H), 3.49 (s, 2H),1.49 (s, 9H).

Step c:

A mixture of tert-butyl1′-oxo-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate (520.0mg, 1.90 mmol), (R)-2-methylpropane-2-sulfinamide (460.0 mg, 3.80 mmol,CAS #196929-78-9) and Ti(OEt)₄ (3.50 g, 15.20 mmol) in 2-Me-THF (10 mL)was stirred at 100° C. for 12 hours. The reaction mixture was used fornext step directly.

Step d:

To a mixture of (R)-tert-butyl1′-((tert-butylsulfinyl)imino)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate(1.90 mmol from Step c) in 2-Me-THF (10 mL) was added L-selectride (2.85mmol, 2.85 mL, 1.0 M in THF, CAS #38721-52-7) slowly at −78° C. Afteraddition, the mixture was stirred at 0° C. for 1 hour. The reactionmixture was then quenched with MeOH (10 mL), poured into EtOAc (500 mL)and H₂O (5 mL), and stirred for 0.5 hour. The mixture was filteredthrough celite and washed with EtOAc (300 mL×2). The filtrate wasconcentrated and purified by silica gel column (EtOAc in petroleumether=30˜50%) to give tert-butyl(1′S)-1′-{[(R)-2-methylpropane-2-sulfinyl]amino}-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate(300.0 mg, 42% yield, the faster eluting isomer) as a light yellow solidand tert-butyl(1′R)-1′-{[(R)-2-methylpropane-2-sulfinyl]amino}-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate(280.0 mg, 39% yield, the slower eluting isomer) as a light yellowsolid. Absolute configuration of the enantiomers was arbitrarilyassigned. Characterization of tert-butyl(1′S)-1′-{[(R)-2-methylpropane-2-sulfinyl]amino}-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate:¹HNMR (400 MHz, DMSO_d₆): δ 7.21-7.45 (m, 4H), 5.91 (br, 1H), 4.63 (d,J=9.6 Hz, 1H), 4.15 (br, 1H), 3.84 (br, 2H), 3.50 (br, 1H), 3.21 (d,J=15.6 Hz, 1H), 3.06 (d, J=15.6 Hz, 1H), 1.35 (s, 9H), 1.18 (s, 9H).LCMS m/z [M+H]⁺=323.1. Characterization of tert-butyl(1′R)-1′-{[(R)-2-methylpropane-2-sulfinyl]amino}-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate:¹H NMR (400 MHz, DMSO_d₆): δ 7.19-7.30 (m, 4H), 5.92 (d, J=8.4 Hz, 1H),4.63 (d, J=9.6 Hz, 1H), 4.23 (br, 1H), 3.84-4.10 (m, 2H), 3.66 (br, 1H),3.27 (d, J=15.6 Hz, 1H), 3.07 (d, J=15.6 Hz, 1H), 1.38 (s, 9H), 1.19 (s,9H). LCMS m/z [M+H]⁺=323.1.

Step e:

A solution of tert-butyl(1′S)-1′-{[(R)-2-methylpropane-2-sulfinyl]amino}-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate(300.0 mg, 792.0 μmol) in 2M HCl/MeOH (20 mL) was stirred at 25° C. for1 hour. The reaction mixture was concentrated to give(1′S)-1′,3′-dihydrospiro[azetidine-3,2′-inden]-1′-amine dihydrochloride(240.0 mg, 123% crude yield) as a light yellow solid.

Step f:

A solution of tert-butyl(1′R)-1′-{[(R)-2-methylpropane-2-sulfinyl]amino}-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate(280.0 mg, 739.0 μmol) in 2M HCl/MeOH (20 mL) was stirred at 25° C. for1 hour. The reaction mixture was concentrated to give(1′R)-1′,3′-dihydrospiro[azetidine-3,2′-inden]-1′-amine dihydrochloride(220.0 mg, 120% crude yield) as a light yellow solid.

(R)-2-methyl-N-[(4S)-1-methyl-4,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-5,4′-piperidin]-4-yl]propane-2-sulfinamide,Intermediate CP

Step a:

A mixture of 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid (4.80 g,23.4 mmol, CAS #84547-84-2) in THE (40.00 mL) was added BH₃/THF (93.60mL, 1 M). The mixture was stirred at 80° C. for 12 hours under N₂atmosphere. To the mixture was added EtOAc (200 mL). The mixture waswashed with saturated NaHCO₃ (200 mL×3). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by column chromatography (petroleum ether:ethylacetate=100:0 to 100:10) to give(4-bromo-1-methyl-1H-pyrazol-5-yl)methanol (4.10 g, 92% yield) as awhite solid. ¹HNMR (400 MHz, DMSO-d₆): δ 7.26 (s, 1H), 4.62 (s, 2H),3.86 (s, 3H).

Step b:

The compound of (4-bromo-1-methyl-1H-pyrazol-5-yl)methanol (3.00 g, 15.7mmol) and CBr₄ (6.23 g, 18.8 mmol) was added in DCM (100 mL). Then PPh₃(4.93 g, 18.8 mmol) in DCM (50 mL) was added dropwise at 0° C. and themixture was stirred at 0° C. for 0.5 h. The reaction was quenched withbrine (100 mL) and the partitioned layers were separated. The aqueousphase was extracted with DCM (100 mL×2). The combined organic layerswere washed with brine (150 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:10) to afford 4-bromo-5-(bromomethyl)-1-methyl-1H-pyrazole (3.20 g,81% yield) as a colorless oil. LCMS m/z [M+H]⁺=252.8, 254.8, 256.8.

Step c:

The compound of tert-butyl 4-cyanopiperidine-1-carboxylate (2.96 g, 14.1mmol) was placed in THE (100 mL). LDA (8.85 mL, 17.7 mmol, 2M in THF)was added dropwise into the mixture at 0° C. and the mixture was stirredat 0° C. for 0.5 h. The mixture was then cooled to −78° C. Then4-bromo-5-(bromomethyl)-1-methyl-1H-pyrazole (3 g, 11.8 mmol) in THE (50mL) was added dropwise into the mixture at −78° C. and the mixture wasstirred at −78° C. for 1 h. The reaction was quenched by addition ofsat. NH₄Cl (100 mL) and the mixture was extracted with ethyl acetate(100 mL×2). The combined organic layers were washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:0 to 100:50) to afford tert-butyl4-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-cyanopiperidine-1-carboxylate(3.30 g, 73% yield) as a white solid. LCMS m/z [M−56+MeCN+H]⁺=368.0,370.0.

Step d:

The compound of tert-butyl4-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-cyanopiperidine-1-carboxylate(1.00 g, 2.6 mmol), PdCl₂(AmPhos) (92.0 mg, 130 μmol) and TEA (1.43 mL,10.4 mmol) were placed into DMA (50.00 mL) and H₂O (1.00 mL). Thereaction mixture was evacuated and refilled 3 times using N₂. Thereaction mixture was stirred at 120° C. for 12 hours. The mixture wasdiluted with ethyl acetate (150 mL), washed with H₂O (50 mL×5), brine(100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated togive a residue. The residue was purified by flash silica gelchromatography (petroleum ether:ethyl acetate=100:50) to affordtert-butyl1-methyl-4-oxo-4,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate(560 mg, 71% yield) as a yellow solid. LCMS m/z [M+H]⁺=306.0.

Step e:

To a solution of tert-butyl1-methyl-4-oxo-4,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-5,4 (200.0 mg,654 μmol) and Ti(OEt)₄ (1.34 mL, 6.54 mmol) in 2-Me-THF (5.00 mL) wasadded (R)-2-methylpropane-2-sulfinamide (316 mg, 2.61 mmol). Thereaction mixture was stirred at 90° C. for 12 h under N₂. The reactionmixture was stirred at 100° C. for another 24 h under N₂. The mixturewas used in next step without directly. LCMS m/z [M+H]⁺=409.1.

Step f:

NaBH₄ (48.0 mg, 1.27 mmol) was added in the mixture of tert-butyl(4Z)-1-methyl-4-{[(R)-2-methylpropane-2-sulfinyl]imino}-4,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate(260.0 mg, 636 μmol) in 2-Me-THF (5.00 ml) at 0° C. The mixture wasstirred at 25° C. for 12 h. The mixture was diluted with ethyl acetate(50 mL). H₂O (20 mL) was added with stirring, a lot of white solidformed. The mixture was filtered. The filtrate was separated, and theaqueous phase was extracted with ethyl acetate (20 mL×2). The combinedorganic phases were washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (petroleum ether:ethylacetate=100:20 to 100:80) to afford tert-butyl(4S)-1-methyl-4-{[(R)-2-methylpropane-2-sulfinyl]amino}-4,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate(150.0 mg, 57% yield) as a yellow oil. LCMS m/z [M+H]⁺=411.1. ¹HNMR (400MHz, CD₃OD): δ 7.53 (s, 1H), 4.35 (s, 1H), 3.90˜4.00 (m, 2H), 3.85 (s,3H), 3.00˜3.30 (m, 2H), 2.86 (s, 2H), 1.60˜2.10 (m, 4H), 1.27 (s, 9H),1.22 (s, 9H).

Step g:

The compound of tert-butyl(4S)-1-methyl-4-{[(R)-2-methylpropane-2-sulfinyl]amino}-4,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-5,4′-piperidine]-1′-carboxylate(150.0 mg, 365 μmol) was added into a solution of TFA (1.00 mL) and DCM(10.00 mL). The mixture was stirred at 25° C. for 1 h. The mixture wasthen adjusted to pH=8-9 with TEA. The mixture was concentrated to give(R)-2-methyl-N-[(4S)-1-methyl-4,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-5,4′-piperidin]-4-yl]propane-2-sulfinamide(200.0 mg, 177% crude yield). LCMS m/z [M+H]⁺=311.1.

(1R)-4,7-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate CO and(1S)-4,7-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,Intermediate CR

Step a:

1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (25.70 g, 106.0 mmol,CAS #124443-68-1) was dissolved in THE (200 mL), and the reactionmixture was cooled to −78° C. Then LDA (57.5 mL, 115.0 mmol) was added,and the reaction mixture was stirred at −78° C. for 2 hours. Then asolution of 2-(bromomethyl)-1,4-difluorobenzene (20.00 g, 96.6 mmol, CAS#85117-99-3) in THE (100 mL) was added, and the reaction mixture waswarmed to 20° C. and stirred for 2 hours. The reaction mixture wasquenched with brine (300 mL), extracted with EtOAc (300 mL×2), theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash silica gelchromatography (petroleum ether:ethyl acetate=100:0 to 100:10) to afford1-tert-butyl 4-methyl4-[(2,5-difluorophenyl)methyl]piperidine-1,4-dicarboxylate (25.00 g, 70%yield) as a yellow oil. LCMS m/z [M+H-Boc]⁺=269.9.

Step b:

1-tert-butyl 4-methyl4-[(2,5-difluorophenyl)methyl]piperidine-1,4-dicarboxylate (25.00 g,67.6 mmol) and KOH (30.20 g, 540 mmol) were added in the mixture of MeOH(150 mL) and H₂O (150 mL), the reaction mixture was stirred at 60° C.for 12 hours. The reaction mixture was concentrated under reducedpressure to about 200 mL, then extracted with petroleum ether (200mL×3). The aqueous phase was adjusted to pH=4 by adding 6N HCl, thenextracted with ethyl acetate (300 mL×3). The combined organic phaseswere washed with brine (200 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to afford1-[(tert-butoxy)carbonyl]-4-[(2,5-difluorophenyl)methyl]piperidine-4-carboxylicacid (20.00 g, 83% yield) as a white solid. LCMS m/z [M+H-Boc]⁺=256.0.

Step c:

1-[(tert-butoxy)carbonyl]-4-[(2,5-difluorophenyl)methyl]piperidine-4-carboxylicacid (10.00 g, 28.1 mmol) was dissolved in 1,2-dichloroethane (200 mL)and the reaction mixture was cooled to 0° C. Then SOCl₂ (4.1 mL, 56.2mmol) was added, and the reaction mixture was warmed to 20° C. andstirred for 4 hours. AlCl₃ (5.60 g, 42.1 mmol) was then added, and thereaction mixture was stirred at 75° C. for 12 hours. The reactionmixture was adjusted to pH=12 by adding 2N NaOH, then (Boc)₂O (9.8 mL,42.1 mmol) was added, and the reaction mixture was stirred at 25° C. for2 hours. The reaction mixture was concentrated under reduced pressure,diluted with EtOAc (500 mL), washed with H₂O (300 mL×3), brine (300 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:0 to 100:20) to afford tert-butyl4,7-difluoro-1-oxo-1,3-dihydrospiro[indene-2,4 (6.50 g, 69% yield) as abrown solid. LCMS m/z [M+H-Boc]⁺=237.8.

Step d:

Tert-butyl 4,7-difluoro-1-oxo-1,3-dihydrospiro[indene-2,4 (2.50 g, 7.4mmol), (R)-2-methylpropane-2-sulfinamide (3.58 g, 29.6 mmol), Ti(OEt)₄(9.3 mL, 44.4 mmol) were added in 2-Me-THF (40 mL), and the reactionmixture was stirred at 90° C. for 48 hours. The reaction mixture wasused in next step without further purification (3.26 g crude product,calculated as theoretical yield). LCMS m/z [M+H]⁺=441.0.

Step e:

Tert-butyl(1Z)-4,7-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]imino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(3.26 g, crude) in 2-Me-THF (40 mL) was cooled to 0° C., then NaBH₄(136.0 mg, 3.7 mmol) was added. The reaction mixture was warmed to 20°C. and stirred for 2 hours. The reaction mixture was then quenched withH₂O (50 mL) and EtOAc (100 mL), filtered and the filter cake was washedwith EtOAc (50 mL×2). The filtrate was washed with H₂O (100 mL×2) andbrine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure and purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:0 to 100:50) to afford tert-butyl4,7-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(2.70 g, 83% yield) as a yellow solid. LCMS m/z [M+H]⁺=443.0. ¹HNMR (400MHz, CDCl₃): δ 6.89-6.74 (m, 2H), 4.57-4.51 (m, 1H), 3.79-3.72 (m, 1H),3.42-3.40 (m, 1H), 3.10-3.01 (m, 4H), 1.86-1.69 (m, 2H), 1.55-1.45 (m,1H), 1.40-1.38 (m, 9H), 1.20-1.16 (m, 1H), 1.13-1.12 (m, 9H). SFC: e.e.=51.36%, Acq. Method Set: AD-3-EtOH-DEA-5-40-25 mL, Vial: 1:E,5, ChannelName: PDA Ch1 220 nm@4.8 nm.

Step f:

Tert-butyl4,7-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4(2.50 g, 5.6 mmol) was purified by prep-HPLC (NH₃.H₂O) to afford theproduct of tert-butyl(1R)-4,7-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4(900.0 mg, 36% yield) as a yellow solid (LCMS m/z [M+H]⁺=443.1; ¹HNMR(400 MHz, DMSO-d₆): δ 7.14-7.04 (m, 2H), 5.63-5.60 (m, 1H), 4.44-4.41(m, 1H), 3.65-3.56 (m, 2H), 3.18-2.85 (m, 3H), 1.71-1.69 (m, 2H),1.41-1.38 (m, 9H), 1.32-1.26 (m, 2H), 1.13-1.12 (m, 9H)) and tert-butyl(1S)-4,7-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4(900.0 mg, 36% yield) as a yellow solid (LCMS m/z [M+H]⁺=443.1; ¹HNMR(400 MHz, DMSO-d₆): δ 7.14-7.04 (m, 2H), 5.79-5.76 (m, 1H), 4.55-4.43(m, 1H), 3.80-3.67 (m, 2H), 3.08-2.82 (m, 4H), 1.76-1.71 (m, 1H),1.56-1.30 (m, 11H), 1.11 (s, 9H)).

Step g:

Tert-butyl(1R)-4,7-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(900.0 mg, 2.0 mmol) was added in 4N HCl/MeOH (20 mL), the reactionmixture was stirred at 25° C. for 2 hours. The white precipitate wascollected by filtration and dried to afford(1R)-4,7-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (500.0 mg, 79% yield) as a white solid. LCMS m/z[M+H]⁺=239.0; ¹HNMR (400 MHz, DMSO-d₆): δ 9.33-9.23 (m, 2H), 8.87 (s,3H), 7.30-7.18 (m, 2H), 4.60 (s, 1H), 3.42-3.33 (m, 2H), 3.12-2.97 (m,4H), 2.24-2.04 (m, 2H), 1.71-1.49 (m, 2H).

Step h:

Tert-butyl(1S)-4,7-difluoro-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(300.0 mg, 677.0 μmol) was added in 4N HCl/MeOH (6 mL), the reactionmixture was stirred at 25° C. for 1 hour. The precipitate was collectedby filtration and dried to give(1S)-4,7-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (150.0 mg, 71% yield) as a white solid. LCMS m/z[M+H]⁺=239.0; ¹HNMR (400 MHz, DMSO-d₆): δ 9.21-9.15 (m, 2H), 8.81 (s,3H), 7.31-7.19 (m, 2H), 4.62 (s, 1H), 3.38-3.33 (m, 2H), 3.17-2.98 (m,4H), 2.22-2.01 (m, 2H), 1.72-1.50 (m, 2H).

tert-butylN-[(3R)-4,7-difluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate CS

Step a:

6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (150.0 mg,411.0 μmol, Intermediate A),(1R)-4,7-difluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (127.0 mg, 411.0 μmol, Intermediate CQ), TEA (283.0 μL,2.1 mmol) were added in DMF (6 mL), and the reaction mixture was stirredat 80° C. for 12 hours. (Boc)₂O (94.3 μL, 411.0 μmol) was added, and thereaction mixture was stirred at 25° C. for 2 hours. The reaction mixturewas concentrated under reduced pressure and purified by flash silica gelchromatography (petroleum ether:ethyl acetate=100:0 to 100:20) to affordtert-butylN-[(3R)-4,7-difluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 73% yield) as a yellow solid. LCMS m/z [M+H]⁺=667.1.

Sodium 2-chloropyridine-3-thiolate, Intermediate CT

Step a:

To a mixture of 2-chloro-3-iodopyridine (1.00 g, 4.17 mmol, CAS#78607-36-0) and 2-ethylhexyl 3-mercaptopropanoate (1.13 g, 5.21 mmol,CAS #50448-95-8) in dioxane (30 mL) were added Pd₂(dba)₃ (317 mg, 347μmol), XantPhos (401.0 mg, 695 μmol) and DIPEA (1.80 mL, 10.4 mmol). Thereaction mixture was purged with N₂ for 3 min and stirred at 100° C. for12 hours under N₂ protection. The reaction mixture was concentratedunder reduced pressure. The residue was purified by columnchromatography (petroleum ether:ethyl acetate=100:0 to 100:20) to give2-ethylhexyl 3-[(2-chloropyridin-3-yl)sulfanyl]propanoate (1.00 g, 88%yield) was as a light yellow solid. LCMS m/z [M+H]⁺=330.1.

Step b:

A mixture of 2-ethylhexyl 3-[(2-chloropyridin-3-yl)sulfanyl]propanoate(500.0 mg, 1.51 mmol) and MeONa (122.0 mg, 2.26 mmol) in THE (5 mL) wasstirred at 0° C. for 1 hour. Then the mixture solution was stirred at20° C. for 1 hour. The mixture was diluted with DCM (5 mL) and stirredfor 0.5 hour, where large amount of solid precipitated. Additional DCMwas added and the solid was collected by filtration to give sodium2-chloropyridine-3-thiolate as a yellow solid (111.0 mg, 44% yield).LCMS m/z [M+H]⁺=218.0.

(R)—N-[(3S)-1′-(6-bromopyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide,Intermediate CU

Step a:

To the mixture of(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(50.0 mg, 163.0 μmol, synthesized via Step a of Example 120) and2-bromo-5-iodopyridine (46.2 mg, 163 μmol, CAS #73290-22-9) in toluene(3.0 mL) were added XantPhos-Pd-G4 (15.6 mg, 16.3 μmol) and Cs₂CO₃(116.0 mg, 358.0 μmol) under N₂. The mixture was stirred at 80° C. underN₂ for 12 hours. The mixture was then concentrated under reducedpressure and the residue was purified by flash silica gel chromatography(DCM/MeOH=1/0 to 10/1) to give(R)—N-[(3S)-1′-(6-bromopyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(60.0 mg, 80% yield) as a brown oil. LCMS m/z [M+H]⁺=462.0.

(R)-2-methyl-N—((R)-1-methylspiro[indoline-2,4′-piperidin]-3-yl)propane-2-sulfinamide,Intermediate CV

Step a:

To the reaction mixture of 2-bromoaniline (10.00 g, 58.1 mmol, CAS#615-36-1) and tert-butyl 4-oxopiperidine-1-carboxylate (11.50 g, 58.1mmol, CAS #79099-07-3) in HOAc (80 mL) was added Me₃SiCN (7.98 mL, 63.9mmol, CAS #7677-24-9) at 25° C. under N₂ atmosphere. The reactionmixture was stirred at 25° C. for 12 hours. The combined reactionmixture was poured into ice-cold NH₄OH solution (500 mL, 28% solution),then extracted with EtOAc (300 mL×2). The combined organic layers werewashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue wastriturated with petroleum ether (100 mL), then filtered to givetert-butyl 4-[(2-bromophenyl)amino]-4-cyanopiperidine-1-carboxylate(19.00 g, 86% yield) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ7.52-7.50 (m, 1H), 7.27-7.24 (m, 1H), 7.20-7.18 (m, 1H), 6.80-6.77 (m,1H), 4.40 (s, 1H), 3.90 (br s, 2H), 3.42-3.35 (m, 2H), 2.37 (br d,J=13.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.47 (s, 9H).

Step b:

The mixture of tert-butyl4-[(2-bromophenyl)amino]-4-cyanopiperidine-1-carboxylate (6.00 g, 15.7mmol), PdCl₂(Amphos)₂ (1.11 g, 1.57 mmol, CAS #887919-35-9) and TEA(8.67 mL, 62.7 mmol) in DMA (120 mL) and H₂O (2.4 mL) was stirred at120° C. for 12 hours under N₂ atmosphere. The reaction mixture wasdiluted with water (120 mL), then extracted with EtOAc (100 mL×3). Theorganic layers were washed with water (80 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashsilica gel chromatography (220 g, EtOAc in petroleum ether from 0% to20%) to give tert-butyl3-oxospiro[indoline-2,4′-piperidine]-1′-carboxylate (1.95 g, 41% yield)as a yellow solid. LCMS m/z [M+Na]⁺=324.9.

Step c:

To the reaction mixture of tert-butyl3-oxospiro[indoline-2,4′-piperidine]-1′-carboxylate (450.0 mg, 1.5 mmol)in THF (9 mL) was added NaHMDS (2.21 mL, 2.2 mmol, 1 M in THF) under N₂atmosphere. The reaction mixture was stirred at 0° C. for 0.5 hour. Then(MeO)₂SO₂ (1.86 g, 14.8 mmol) was added and the resulting mixture wasstirred at 0° C. for 0.5 hour. The combined reaction mixture was pouredinto saturated NaHCO₃ (40 mL) and extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by flash silica gelchromatography (40 g, EtOAc in petroleum ether from 0% to 15%) to givethe product (1.4 g) as a yellow oil. Then NaOH solution (20 mL, 4 M inwater) was added into the residue, and the mixture was stirred at 25° C.for 1 hour. The mixture was then extracted with EtOAc (50 mL×2). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give tert-butyl1-methyl-3-oxospiro[indoline-2,4′-piperidine]-1′-carboxylate (500.0 mg,quant. crude yield) as a green oil. LCMS m/z [M+Na]⁺=338.9; ¹HNMR (400MHz, CDCl₃) δ 7.57 (d, J=7.6 Hz, 1H), 7.49-7.45 (m, 1H), 6.74-6.66 (m,2H), 4.14-3.97 (m, 2H), 3.67-3.65 (m, 2H), 2.89 (s, 3H), 1.88 (br s,2H), 1.53-1.38 (m, 12H).

Step d:

The reaction mixture of tert-butyl1-methyl-3-oxo-1,3-dihydrospiro[indole-2,4′-piperidine]-1′-carboxylate(600.0 mg, 1.9 mmol), (R)-2-methylpropane-2-sulfinamide (916.0 mg, 7.6mmol) and Ti(OEt)₄ (6 mL) was stirred at 100° C. for 12 hours under N₂atmosphere. The addition of (R)-2-methylpropane-2-sulfinamide (916.0 mg,7.6 mmol) at 100° C. was repeated one time. The resulting mixture wasstirred at 100° C. for 20 hours. The combined reaction mixture wasquenched with EtOAc (50 mL) and H₂O (50 mL). The reaction mixture wasfiltered, and the filter cake was washed with EtOAc (50 mL×2). Thefiltrate was separated and the aqueous was extracted with EtOAc (50mL×2). The combined organic layers were washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by flash silica gelchromatography (40 g, EtOAc in petroleum ether from 0% to 33%) to givetert-butyl(3E)-1-methyl-3-{[(R)-2-methylpropane-2-sulfinyl]imino}-1,3-dihydrospiro[indole-2,4′-piperidine]-1′-carboxylate(190.0 mg, 20% yield) as a yellow solid. LCMS m/z [M+H]⁺=420.1.

Step e:

To a mixture of tert-butyl(3E)-1-methyl-3-{[(R)-2-methylpropane-2-sulfinyl]imino}-1,3-dihydrospiro[indole-2,4′-piperidine]-1′-carboxylate(190.0 mg, 0.4 mmol) in 2-Me-THF (4 mL) was added NaBH₄ (170.0 mg, 4.5mmol) and MeOH (1 mL) at 25° C. The mixture was stirred at 40° C. for0.5 hour. The reaction mixture was quenched with MeOH (1 mL) and pouredinto the mixture of H₂O (50 mL) and EtOAc (60 mL). The mixture wasseparated and the aqueous was extracted with EtOAc (60 mL×2). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by prep-TLC (petroleum ether/EtOAc=1/1) toafford tert-butyl(3R)-1-methyl-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indole-2,4′-piperidine]-1′-carboxylate(157.0 mg, 83% yield) as a yellow solid. LCMS m/z [M+Na]⁺=444.1; ¹H NMR(400 MHz, CDCl₃) δ 7.22-7.17 (m, 2H), 6.71 (t, J=7.6 Hz, 1H), 6.46 (d,J=8.0 Hz, 1H), 4.61 (d, J=9.2 Hz, 1H), 4.36-4.20 (m, 2H), 3.61 (br d,J=9.2 Hz, 1H), 3.18-2.92 (m, 2H), 2.01-1.88 (m, 1H), 1.47-1.46 (m, 11H),1.28-1.23 (m, 1H), 1.17 (s, 9H).

Step f:

To the reaction mixture of tert-butyl(3R)-1-methyl-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indole-2,4′-piperidine]-1′-carboxylate(157.0 mg, 0.4 mmol) in DCM (4 mL) was added TFA (0.4 mL). The reactionmixture was stirred at 25° C. for 0.5 hour, and then stirred at 40° C.for 0.5 hour. The reaction mixture was adjusted to pH=7-8 with TEA. Themixture was then concentrated to give(R)-2-methyl-N—((R)-1-methylspiro[indoline-2,4′-piperidin]-3-yl)propane-2-sulfinamide(119.0 mg, quant. crude yield) as a yellow oil. LCMS m/z [M+H]⁺=321.9.

tert-butyl(S)-(1′-(7-bromothieno[3,2-d]pyrimidin-4-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate CW

Step a:

The compound of 4-chlorothieno[3,2-d]pyrimidine (800 mg, 4.68 mmol, CAS#16269-66-2), NBS (1.05 g, 4.68 mmol) and HOAc (0.2 mL) were added inMeCN (20 mL). The mixture was stirred at 85° C. for 18 h. The mixturewas then extracted with ethyl acetate (30 mL×3). The combined organiclayers were washed with brine (20 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byflash silica gel chromatography (ethyl acetate/petroleum ether=0/100 to15/100) to afford 7-bromo-4-chlorothieno[3,2-d]pyrimidine (229 mg, 20%yield) as a white solid. LCMS m/z [M+H]⁺=250.8; ¹HNMR 2 (400 MHz, CDCl₃)δ 9.14 (s, 1H), 8.09 (s, 1H).

Step b:

The compound of 7-bromo-4-chlorothieno[3,2-d]pyrimidine (210 mg, 841μmol), (S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (254 mg, 925 μmol, Intermediate I) and TEA (582 μL, 4.20mmol) were placed into DMF (10 mL). The reaction mixture was evacuatedand refilled 3 times using N₂. The reaction mixture was stirred at 85°C. for 12 hours. The reaction mixture was concentrated and H₂O (30 mL)was added and the mixture was extracted with ethyl acetate (100 mL). Thecombined organic layers were washed with H₂O (20 mL×5) and brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue as a yellow solid (330 mg, 94% yield). LCMS m/z [M+H]⁺=415.0.

Step c:

The compound of(3S)-1(S)-1′-(7-bromothieno[3,2-d]pyrimidin-4-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(330 mg, 794 μmol), TEA (400 mg, 4.0 mmol) and (Boc)₂O (519 mg, 2.4mmol) were placed into DMF (10 mL). The reaction mixture was stirred at25° C. for 2 hours. The reaction mixture was concentrated and H₂O (20mL) was added, then extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (petroleum ether:ethylacetate=100:0 to 100:40) to afford tert-butyl(S)-(1′-(7-bromothieno[3,2-d]pyrimidin-4-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(240.0 mg, 59% yield) as a white solid. LCMS m/z [M+H]⁺=517.0.

(6-((R)-3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate, Intermediate

Step a:

To a solution of (R)-3H-spiro[benzofuran-2,4′-piperidin]-3-aminedihydrochloride (230 mg, 0.8 mmol, Intermediate CB) and[6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methylacetate (361 mg, 0.8 mmol, Intermediate C) in DMF (5.0 mL) was added TEA(573 μL, 4.1 mmol). The reaction was stirred at 70° C. for 12 hours.Then to the solution was added (Boc)₂O (379 uL, 1.7 mmol) and thereaction was stirred at 70° C. for another 2 hours. The reaction mixturewas concentrated under reduced pressure to give a residue which waspurified by column chromatography (petroleum ether:ethyl acetate=100:0to 100:20).(6-((R)-3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate (550 mg, 94% yield) was obtained as a white solid. LCMS m/z[M+H]⁺=705.0.

(R)—N-((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide,Intermediate CY

Step a:

A solution of 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine(12 g, 32.9 mmol, Intermediate A),(R)—N—((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(10.0 g, 32.9 mmol, synthesized via Step a of Example 120) and CsF (14.9g, 98.6 mmol) in DMSO (150 mL) was stirred at 60° C. for 2 h. Thereaction mixture was poured into H₂O (700 mL) and extracted with EtOAc(700 mL×2). The combined organic layers were washed with brine (800 mL),dried over anhydrous Na2SO4, filtered and filtrate concentrated underreduced pressure to give an orange residue. The residue was purified byflash silica gel chromatography (220 g, ethyl acetate in petroleum etherfrom 0% to 50%) to give(R)—N-((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(12.5 g, 60% yield) as a yellow solid. LCMS m/z [M+H]⁺=635.0;

¹HNMR (400 MHz, CD₃OD): 8.31 (s, 1H), 7.33-7.36 (m, 1H), 7.22-7.27 (m,3H), 5.78-5.83 (m, 1H), 4.62 (s, 1H), 4.46-4.55 (m, 3H), 4.03-4.06 (m,1H), 3.72-3.77 (m, 1H), 3.34-3.37 (m, 1H), 3.23-3.27 (m, 1H), 2.82-2.87(m, 1H), 2.54-2.58 (m, 1H), 2.10-2.19 (m, 2H), 1.90-1.93 (m, 2H),1.68-1.80 (m, 4H), 1.52-1.64 (m, 1H), 1.31 (s, 9H).

tert-butylN-[(3S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate CZ

Step a:

To a solution of(3S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(1.30 g, 3.6 mmol, Intermediate CI) in DMF (15 mL) was added Boc₂O (1.65mL, 7.22 mmol). The resulting mixture was stirred at 25° C. for 12hours. The reaction mixture was diluted with water (30 mL), thenextracted with EtOAc (50 mL×2). The organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (40 g column,EtOAc in petroleum ether from 0% to 15%) to give tert-butylN-[(3S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(815 mg, 50% yield) as a yellow solid. LC-MS (M+H)⁺m/z=459.0.

1-benzyl-6-chloro-3-[(2,3-dichlorophenyl)sulfanyl]-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,Intermediate DA

Step a:

To a mixture of1-benzyl-3-iodo-7-[(4-methoxyphenyl)methyl]-5-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-d]pyrimidine-4,6-dione(2.00 g, 4.0 mmol, CAS #2055938-41-3) and 2,3-dichlorobenzene-1-thiol(1.06 g, 6.0 mmol) in dioxane (20 mL) were added Pd₂(dba)₃ (291 mg, 0.4mmol), XantPhos (370.0 mg, 0.8 mmol) and DIPEA (1.4 mL, 8.0 mmol). Themixture was evacuated and refilled 3 times using N₂ and stirred at 120°C. for 10 hours. The mixture was then concentrated under reducedpressure to give a residue and purified by flash silica gelchromatography (petroleum ether:ethyl acetate=100:0 to 100:30) to afford1-benzyl-3-[(2,3-dichlorophenyl)sulfanyl]-7-[(4-methoxyphenyl)methyl]-5-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-d]pyrimidine-4,6-dione(1.00 g, 45% yield) as a light red solid. LC-MS (M+H)⁺m/z=552.9.

Step b:

A solution of1-benzyl-3-[(2,3-dichlorophenyl)sulfanyl]-7-[(4-methoxyphenyl)methyl]-5-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-d]pyrimidine-4,6-dione(950.0 mg, 1.7 mmol) in TfOH (0.2 mL) and TFA (20 mL) was stirred at 70°C. for 1 hour. The reaction mixture was diluted with DCM (30 mL),concentrated under reduced pressure to give a residue. The residue wasdiluted with H₂O (10 mL), adjusted to pH=9˜10 by adding aq. NaOH (1N)and extracted with ethyl acetate (50 mL×3). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was triturated withpetroleum ether and ethyl acetate (10:1) where a lot of precipitateformed. The solid was collected by filtration, and the filter cake waswashed with petroleum ether:ethyl acetate=(10:1, 20 mL), then dried togive1-benzyl-3-[(2,3-dichlorophenyl)sulfanyl]-5-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-d]pyrimidine-4,6-dione(740.0 mg, 100% yield) as a light brown solid. ¹HNMR (400 MHz, CDCl₃):8.75 (s, 1H), 7.11-7.18 (m, 5H), 6.87-6.92 (m, 1H), 6.62-6.65 (m, 1H),5.41 (s, 2H), 3.25 (s, 3H).

Step c:

To a mixture of1-benzyl-3-[(2,3-dichlorophenyl)sulfanyl]-5-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-d]pyrimidine-4,6-dione(300.0 mg, 0.7 mmol) and DIPEA (1.2 mL, 6.9 mmol) was added POCl₃ (1.7mL, 18.5 mmol). The reaction mixture was stirred at 120° C. for 12hours. The reaction mixture was concentrated under reduced pressure togive a residue which was diluted with ethyl acetate (50 mL). The mixturewas added slowly into ice-cooled sat. NaHCO₃ (30 mL) and the partitionedlayers were separated. The aqueous phase was extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:50) to afford1-benzyl-6-chloro-3-[(2,3-dichlorophenyl)sulfanyl]-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(220.0 mg, 71% yield) as a yellow solid. LC-MS (M+H)⁺ m/z=450.9.

(3S)-1′-{3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine,Intermediate DB

Step a:

A solution of tert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(500.0 mg, 792.0 μmol, Intermediate J), 10% Pd/C (100.0 mg) and TEA(220.0 μL, 1.58 mmol) in THF (15.0 ml) was stirred at 20° C. for 12hours under H₂ (15 psi). The reaction mixture was filtered and thefiltrate was concentrated to give tert-butylN-[(3S)-1′-[1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(380.0 mg, 95% yield) as a yellow solid. LCMS (ESI⁺) m/z: 505.1 (M+H)⁺.

Step b:

To a solution of tert-butylN-[(3S)-1′-[1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(380.0 mg, 753.0 μmol) in AcOH/ACN (10.0 mL/10.0 mL) was added NBS(134.0 mg, 753.0 μmol). The reaction mixture was stirred at 20° C. for0.5 hour. The reaction mixture was then concentrated under reducedpressure. The residue was triturated with H₂O (100.0 mL) and extractedwith EtOAc (100.0 mL×2). The combined organic layers were washed withsat. NaHCO₃ (100.0 mL), dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure to give a residue. Theresidue was purified by flash silica gel chromatography (12 g column,ethyl acetate in petroleum ether from 0% to 20%) to give tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(330.0 mg, 75% yield) as a white solid. LCMS (ESI⁺) m/z: 583.0 (M+H)⁺.

Step c:

A solution of tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(330.0 mg, 565.0 μmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (141.0mg, 1.13 mmol, CAS #823-96-1), Pd(dppf)Cl₂ (82.7 mg, 113.0 umol, CAS#72287-26-4) and K₂CO₃ (233.0 mg, 1.69 mmol) in dioxane/H₂O (10.0 mL/2.0mL) was stirred at 90° C. for 12 hours under N₂. The reaction mixturewas poured into H₂O (100.0 mL) and extracted with EtOAc (100.0 mL×2).The combined organic layers were washed with brine (200.0 mL), driedover anhydrous Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (12 g column, ethyl acetate in petroleum etherfrom 0% to 30%) to give tert-butylN-[(3S)-1′-[5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 85% yield) as a yellow oil. LCMS (ESI⁺) m/z: 519.2 (M+H)⁺.

Step d:

A solution of tert-butylN-[(3S)-1′-[5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 482.0 μmol) in HCl/MeOH (15.0 mL, 4 M) was stirred at 20° C.for 1 hour. The reaction mixture was then concentrated, triturated withEtOAc and stirred for 20 min. The mixture was filtered and the filtercake was concentrated to give(S)-1′-(5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (180.0 mg, 101% crude yield) as a yellow solid. LCMS(ESI⁺) m/z: 335.1 (M+H)⁺.

Step e:

The compound of(3S)-1′-{5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (100.0 mg, 269.0 μmol) and TEA (111 μL, 807.0 μmol) wasdissolved in DCM (10 ml). Then (Boc)₂O (73.8 μL, 322.0 μmol) in DCM(0.13 mL) was added. The mixture was stirred at 25° C. for 2 hours. Themixture was washed with H₂O (10 mL×2), brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether:ethyl acetate=100:0 to 100:30) to give tert-butylN-[(3S)-1′-{5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(70.0 mg, 60% yield) as a yellow oil. LCMS (ESI⁺) m/z: 435.1 (M+H)⁺.

Step f:

Tert-butylN-[(3S)-1′-{5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(70.0 mg, 161.0 μmol) and NIS (54.2 mg, 241.0 μmol) were added in DMF (2mL). The reaction mixture was stirred at 110° C. for 16 hours. Themixture was quenched with the mixture of sat. Na₂SO₃ (10 mL) and sat.NaHCO₃ (10 mL) and stirred for 10 min where a lot of precipitate formed.Then H₂O (10 mL) was added and the mixture was stirred for 1 min, thenextracted with ethyl acetate (10 mL×3). The combined organic layers werewashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give(3S)-1′-{3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(60.0 mg, 81% yield) as a brown solid. LCMS (ESI⁺) m/z: 461.0 (M+H)⁺.

4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine, Intermediate DC and4-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidine, Intermediate DD

Step a:

4-Chloro-2H-pyrazolo[3,4-d]pyrimidine (1.00 g, 6.5 mmol, CAS #5399-92-8)was dissolved in THE (33.0 mL). Then NaHMDS (10 mL, 1.0 M in THF) wasadded at 0° C. and the mixture was stirred for 5 min. Mel (1.03 mL, 16.7mmol) was added slowly over 5 min at 0° C. under N₂ gas protection. Thereaction mixture was warmed to 25° C. and stirred for 1 h. The mixturewas diluted with H₂O (200 mL) and CH₂Cl₂ (200 mL), then the partitionedlayers were separated. The aqueous phase was extracted with CH₂Cl₂ (50mL×3). The combined organic layers were washed with brine (200 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(ethyl acetate:petroleum ether=0:100 to 100:100) to afford4-chloro-1-methyl-1H-pyrazolo[3,4d]-dipyrimidine (98.3 mg, 9.1% yield)as a yellow solid (LCMS (ESI+) m/z: 169 (M+H)⁺; ¹HNMR (400 MHz, DMSO-d₆)δ 8.87 (s, 1H), 8.47 (s, 1H), 4.09 (s, 3H)) and4-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidine (242 mg, 22% yield) as ayellow solid (LCMS (ESI+) m/z: 169 (M+H)⁺; ¹HNMR (400 MHz, DMSO-d₆) δ8.91 (s, 1H), 8.80 (s, 1H), 4.25 (s, 3H)).

Sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate,Intermediate DE

Step a:

A mixture of (S)-tert-butyl(1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(590.0 mg, 1.3 mmol, Intermediate CZ), 2-ethylhexyl 3-mercaptopropanoate(334.0 mg, 1.5 mmol, CAS #50448-95-8), Pd₂(dba)₃ (117.0 mg, 0.13 mmol),XantPhos (148.0 mg, 0.26 mmol, CAS #161265-03-8) and TEA (522 μL, 3.8mmol) in toluene (15 mL) was stirred at 100° C. for 12 hours under N₂atmosphere. The reaction mixture was then concentrated to give aresidue. The residue was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 15%) to afford 2-ethylhexyl3-((5-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(690 mg, 90% yield) as a yellow oil. LCMS (ESI+) m/z: 597.2 (M+H)⁺.

Step b:

To a mixture of 2-ethylhexyl3-((5-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(690.0 mg, 1.2 mmol) in anhydrous THE (10 mL) was added MeONa (124.0 mg,2.3 mmol). The resulting mixture was stirred at 20° C. for 3 hours underN₂ atmosphere. The reaction mixture was then concentrated to give thecrude product, which was triturated with petroleum ether:ethylacetate=10:1 (50 mL). The solid was collected and dried in vacuo toafford sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate(500.0 mg, 100% yield) as a red solid. LCMS (ESI⁺) m/z: 413.1 (M−Na+H)⁺.

4-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one,Intermediate DF

Step a:

The compound of1-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine(4.00 g, 10.7 mmol, Intermediate AA),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carbonitrile(2.72 g, 11.7 mmol, CAS #1310384-20-3), Pd(dppf)Cl₂ (782.0 mg, 1.1 mmol)and Cs₂CO₃ (6.97 g, 21.4 mmol) were placed into the solvent of dioxane(250 mL) and H₂O (25 mL). The reaction mixture was evacuated andrefilled for 3 times using N₂; then the reaction mixture was stirred at90° C. for 12 hours. The reaction mixture was then concentrated and H₂O(200 mL) was added, then the mixture was extracted with ethyl acetate(300 mL×3). The combined organic layers were washed with brine (500 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:50 to 100:90) to afford4-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]cyclohex-3-ene-1-carbonitrile(4.70 g, 99.5% yield) as a yellow solid. LCMS (ESI⁺) m/z: 442.1 (M+H)⁺.

Step b:

4-[1-(Oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]cyclohex-3-ene-1-carbonitrile(2.70 g, 6.1 mmol) and 1-bromo-2-(bromomethyl)benzene (1.67 g, 6.7 mmol)were dissolved in THE (150 mL). Then LDA (3.66 mL, 7.3 mmol, 2 M in THF)was added dropwise into the mixture at −10° C. The mixture was stirredat 0° C. for 0.5 hour, then warmed to 25° C. for 1 hour. Next, anotherLDA (3.66 mL, 7.3 mmol), 2 M in THF) was added dropwise into the mixtureat 0° C. The mixture was stirred at 0° C. for 0.5 hour, then warmed to25° C. for 1 hour. The reaction mixture was quenched by addition ofsaturated NH₄Cl (200 mL), then the mixture was extracted with ethylacetate (200 mL×3). The combined organic layers were washed with brine(300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to givea residue. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:20 to 100:80) to afford1-[(2-bromophenyl)methyl]-4-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]cyclohex-3-ene-1-carbonitrile(1.70 g, 26% yield) as a yellow solid. LCMS (ESI⁺) m/z: 610.0, 612.0(M+H)⁺.

Step c:

1-[(2-Bromophenyl)methyl]-4-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]cyclohex-3-ene-1-carbonitrile(700.0 mg, 1.1 mmol), PdCl₂(AmPhos)₂ (23.1 mg, 32.6 μmol) and TEA (631μL, 4.6 mmol) were placed into DMA (25 mL) and H₂O (0.5 mL). Thereaction mixture was evacuated and refilled 3 times using N₂. Thereaction mixture was stirred at 120° C. for 12 hours. The mixture wasthen diluted with ethyl acetate (100 mL). The mixture was washed withH₂O (30 mL×5), brine (50 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:50 to100:80) to afford4-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one(520 mg, 86% yield) as a yellow oil. LCMS (ESI⁺) m/z: 533.1 (M+H)⁺.

4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine, Intermediate DG and4-chloro-3-methyl-3H-imidazo[4,5-c]pyridine, Intermediate DH

Step a:

To a solution of 4-chloro-3H-imidazo[4,5-c]pyridine (1 g, 6.51 mmol, CAS#81053-66-9) in DMSO/THF (2.5 mL/25 mL) was added NaHMDS (9.76 mL, 9.76mmol) at 20° C. under N₂. The reaction mixture was stirred at 20° C. for1 h. Then, to the reaction mixture was added Mel (1.21 mL, 19.5 mmol) at20° C. The reaction mixture was then stirred at 20° C. for 11 h. Thereaction mixture was filtered and the filtrate was concentrated to givea residue. The residue was purified by prep-HPLC (NH₃.H₂O) to give4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine (Intermediate DG) (257.2 mg,24% yield) as a white solid, LCMS (ESI+) m/z: 167.8 (M+H)⁺; ¹HNMR (400MHz, DMSO-d₆) δ 8.16˜8.14 (m, 1H), 7.92 (s, 1H), 7.27˜7.25 (m, 1H), 3.71(s, 3H), and 4-chloro-3-methyl-3H-imidazo[4,5-c]pyridine (IntermediateDH) (201.8 mg, 19% yield) as a white solid, LC-MS (ESI+) m/z: 167.8(M+H)⁺, ¹HNMR (400 MHz, DMSO-d₆) δ 8.34˜8.13 (m, 1H), 7.98 (m, 1H),7.79˜7.54 (m, 1H), 7.29 (m, 1H), 4.34˜4.09 (m, 3H).

2-chloro-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine, Intermediate DI

Step a:

A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 40.6 mmol, CAS#183208-35-7), cyclopropylboronic acid (8.01 g, 93.3 mmol) and K₂CO₃(16.60 g, 121.0 mmol) in toluene (100.0 mL) was stirred at 25° C. for0.5 hours under N₂ atmosphere. Then, Pd₂(dba)₃ (1.85 g, 2.0 mmol) andSPhos (1.66 g, 4.1 mmol) were added, and the resulting mixture wasstirred at 100° C. for 11.5 hours under N₂ atmosphere. The reactionmixture was then concentrated in vacuo to give a residue, which was thendissolved in ethyl acetate (200.0 mL), and washed with H₂O (150.0 mL×3).The organic phase was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 35%) to afford5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (2.70 g, 42% yield) as a yellowsolid. LC-MS (ESI⁺) m/z 159.0 (M+H)⁺.

Step b:

To a stirring solution of 5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (2.10g, 13.2 mmol) in t-BuOH (120.0 mL) was added pyridium tribromide (12.50g, 39.5 mmol) portion-wise, then the resulting mixture was stirred at25° C. for 12 hours. The reaction mixture was concentrated in vacuo togive a residue, which was then dissolved in ethyl acetate (200.0 mL) andwashed with H₂O (150.0 mL×2). The organic phase was washed with brine(50.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford3,3-dibromo-5-cyclopropyl-1H,2H,3H-pyrrolo[2,3-b]pyridin-2-one (4.3 g,crude product) as a yellow solid. LC-MS (ESI⁺) m/z 330.9 (M+H)⁺.

Step c:

To a mixture of3,3-dibromo-5-cyclopropyl-1H,2H,3H-pyrrolo[2,3-b]pyridin-2-one (4.30 g,12.9 mmol) in AcOH (20.0 mL) and MeOH (20.0 mL) was added Zn (4.21 g,64.5 mmol), and the resulting mixture was stirred at 25° C. for 2 hours.The reaction mixture was then filtered and concentrated in vacuo to givea residue, which was then dissolved in ethyl acetate (100.0 mL), andwashed with H₂O (80.0 mL×2). The organic phase was washed with brine(25.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give a residue, which was triturated with EtOH (20 mL) toafford 5-cyclopropyl-1H,2H,3H-pyrrolo[2,3-b]pyridin-2-one (1.50 g, 67%yield) as a brown solid. LC-MS (ESI⁺) m/z 174.9 (M+H)⁺.

Step d:

A mixture of 5-cyclopropyl-1H,2H,3H-pyrrolo[2,3-b]pyridin-2-one (700.0mg, 4.0 mmol) in POCl₃ (6.50 mL, 69.9 mmol) was stirred at 110° C. for 4hours. The reaction mixture was then concentrated in vacuo to give aresidue, which was dissolved in DCM (20.0 mL) and adjusted to pH=8 withsaturated Na₂CO₃, then extracted with DCM (25.0 mL×3). The organicphases were washed with brine (25.0 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (ethyl acetate in petroleumether=0% to 35%) to afford2-chloro-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (410.0 mg, 34% yield)as a yellow solid. LC-MS (ESI⁺) m/z 193.0 (M+H)⁺.

tert-butylN-[(3S)-1′-(5-sulfanylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate DJ

Step a:

A mixture of 2,5-dibromopyrazine (4.00 g, 16.8 mmol, CAS #23229-26-7),(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(5.06 g, 18.4 mmol, Intermediate I) and TEA (11.6 mL, 84.0 mmol) in DMF(50 mL) was stirred at 80° C. for 3 hours. The crude solution was thencooled to rt and used directly in the next step. LC-MS (ESI⁺) m/z:341.9, 343.9 (M−NH₂)⁺.

Step b:

To the crude solution of(S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(6.03 g, 16.7 mmol) in DMF (50 mL) was added (Boc)₂O (5.73 mL, 25.0mmol). The resulting mixture was stirred at 25° C. for 12 hours. Thenthe mixture was diluted with EtOAc (500 mL). The mixture was next washedwith H₂O (100 mL×5), brine (500 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified bysilica gel chromatography (ethyl acetate in petroleum ether=0% to 15% toafford (S)-tert-butyl(1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(7.60 g, 99% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 459.2, 461.2(M+H)⁺.

Step c:

(S)-tert-butyl(1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(3.00 g, 6.53 mmol), 2-ethylhexyl 3-sulfanylpropanoate (1.56 g, 7.18mmol, CAS #50448-95-8), XantPhos (752 g, 1.30 mmol), Pd₂(dba)₃ (597.0mg, 0.65 mmol), and DIPEA (3.40 mL, 19.5 mmol) were added into dioxane(60 mL). The reaction mixture was evacuated and refilled 3 times withN₂. The solution was stirred at 100° C. for 12 h. The solvent was thenremoved under reduced pressure. The residue was triturated with DCM (100mL) and H₂O (100 mL), and the yellow solid was filtered off. The organiclayer was separated and the aqueous layer was extracted with DCM (100mL×2). The combined organic layers were washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give a brownresidue. The residue was purified by flash column chromatography(petroleum ether/EtOAc=100:0 to 100:15) to afford 2-ethylhexyl3-[({5-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4(3.0 g, 77% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 597.2 (M+H)⁺.

Step d:

The compound of 2-ethylhexyl3-({5-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)propanoate(200.0 mg, 335 μmol) was dissolved in THE (1.00 mL). The reactionmixture was cooled to −78° C. and t-BuOK (1.00 mL, 1 M in THF) was addeddropwise over 10 min under N₂. The reaction mixture was stirred at −78°C. for 20 min. The reaction mixture was diluted with DCM (30 mL) andacidified with HCl/MeOH (2 N) to pH=6 at −78° C. The mixture was washedwith H₂O (20 mL) and brine (20 ml). The organic layer were dried overanhydrous Na₂SO₄, filtered and concentrated to give tert-butylN-[(3S)-1′-(5-sulfanylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(138.0 mg, 100% yield, crude) as a yellow oil.

Sodium5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylpyrazine-2-thiolate,Intermediate DK, and sodium5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methylpyrazine-2-thiolate,Intermediate DL

Step a:

A mixture of(R)—N—((S)-1′-(5-bromo-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-1′-(5-bromo-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(320.0 mg, 670.0 μmol, synthesized via Step a of Examples 83 and 84),2-ethylhexyl 3-sulfanylpropanoate (292.0 mg, 1.3 mmol, CAS #50448-95-8),XantPhos (77.5 mg, 134.0 μmol), DIPEA (344.0 μL, 2.0 mmol) and Pd₂(dba)₃(61.3 mg, 67.0 μmol) in 1,4-dioxane (15.0 mL) was stirred at 110° C. for12 hours under N₂ atmosphere. The reaction mixture was concentrated invacuo to give a residue, which was purified by silica gel chromatography(ethyl acetate in petroleum ether=0% to 55%) to afford 2-ethylhexyl3-((5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylpyrazin-2-yl)thio)propanoateand 2-ethylhexyl3-((5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methylpyrazin-2-yl)thio)propanoate(400.0 mg) as a yellow oil. LC-MS (ESI⁺) m/z 615.2 (M+H)⁺.

Step b:

To a mixture of 2-ethylhexyl3-((5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylpyrazin-2-yl)thio)propanoateand 2-ethylhexyl3-((5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methylpyrazin-2-yl)thio)propanoate(390.0 mg, 634.0 μmol) in anhydrous THF (10.0 mL) was added MeONa (68.0mg, 1.3 mmol), and the resulting mixture was stirred at 20° C. for 1hour under N₂ atmosphere. The reaction mixture was concentrated in vacuoto give a residue, which was triturated with petroleum ether:ethylacetate=10:1 (20 mL) and filtered. The solids were combined and driedunder vacuum to afford sodium5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylpyrazine-2-thiolateand sodium5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methylpyrazine-2-thiolate(260 mg, 91% yield) as a yellow solid. LC-MS (ESI⁺) m/z 431.1 (M+H-Na)⁺.

2-Chloro-1-cyclopentylethan-1-one, Intermediate DM

Step a:

To a mixture of cyclopentanecarboxylic acid (3.00 g, 26.2 mmol) in SOCl₂(10.0 mL) was added DMF (2 drops), and the resulting mixture was stirredat 50° C. for 3 hours under N₂ atmosphere. The mixture was concentratedin vacuo to give a residue, which was dissolved in DCM (30.0 mL) andthen re-concentrated in vacuo to give cyclopentanecarbonyl chloride(3.40 g, 98% crude yield) as a colorless oil.

Step b:

To a mixture of cyclopentanecarbonyl chloride (3.40 g, 25.6 mmol) inanhydrous THF (60.0 mL) at 0° C. was added TMSCHN₂ (38.4 mL, 76.8 mmol)slowly, then the mixture was stirred at this temperature for 0.5 hours.Then the resulting mixture was warmed to 20° C. and stirred for 11.5hours. The mixture was concentrated in vacuo to give a residue, whichwas then dissolved in THE (60.0 mL) and HCl/1,4-dioxane (4 M, 19.2 mL)was added slowly at 0° C. The resulting mixture was warmed to 20° C. andstirred for 2 hours. The mixture was then concentrated in vacuo to givea residue, which was dissolved in ethyl acetate (50.0 mL), and washedwith sat.NaHCO₃ (30.0 mL). The organic phase was washed with brine (20.0mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by silica gel chromatography(ethyl acetate in petroleum ether=0% to 5%) to afford2-chloro-1-cyclopentylethan-1-one (2.50 g, 67% yield) as a yellow oil.¹HNMR (400 MHz, CDCl₃): δ 4.16 (s, 2H), 3.14-3.06 (m, 1H), 1.87-1.59 (m,8H).

Methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate,Intermediate DN

Step a:

Methyl 6-bromo-3-chloropyrazine-2-carboxylate (3 g, 11.9 mmol, CAS#1256921-67-1), TEA (8.26 mL, 59.5 mmol) and(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine dihydrochloride(3.27 g, 11.9 mmol, Intermediate I) were placed into DMF (80 mL). Thereaction mixture was evacuated and refilled 3 times using N₂. Thereaction mixture was then stirred at 50° C. for 2 hours. The mixture wasused for the next step without further purification. LC-MS (ESI⁺) m/z:440.8 (M+Na)⁺.

Step b:

Methyl3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-bromopyrazine-2-carboxylate(4.96 g, 11.8 mmol), TEA (8.20 mL, 59.0 mmol) and (Boc)₂O (7.72 g, 35.4mmol) were placed into DMF (80 mL). The reaction mixture was stirred at25° C. for 2 hours. Then the combined mixture was diluted with EtOAc (1L), washed with H₂O (300 mL×5), brine (800 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (ethyl acetate/petroleumether=0/100 to 20/100) to afford methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(7.67 g, combined product) as a yellow oil. LC-MS (ESI⁺) m/z: 425.2(M−NHBoc+Na)⁺.

Tert-butylN-[(3S)-1′-(5-bromo-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate DO

Step a:

Methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(500.0 mg, 966 μmol, Intermediate DN) and NaOH (386 mg, 9.66 mmol) wereplaced into MeOH/H₂O=5 mL/5 mL. The reaction mixture was stirred at 25°C. for 12 hours. The reaction mixture was concentrated and extractedwith ethyl acetate (40 mL×2) and the partitioned layers were separated.The combined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylicacid (600 mg, 1.19 mmol, quant. crude yield) as a yellow solid. LC-MS(ESI⁺) m/z: 503.0 (M+H)⁺.

Step b:

A mixture of6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylicacid (600.0 mg, 1.19 mmol), DIPEA (1.83 g, 14.2 mmol), HATU (676 mg,1.78 mmol) and DMF (10 mL) was stirred at 25° C. for 1 h. Then NH₄Cl(631 mg, 11.8 mmol) was added, and the resulting mixture was stirred at25° C. for 12 h. The mixture was then diluted with EtOAc (200 mL). Themixture was washed with H₂O (60 mL×5), brine (200 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give tert-butylN-[(3S)-1′-(5-bromo-3-carbamoylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(480 mg, 80% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 504.0 (M+H)⁺.

Step c:

To a reaction mixture of tert-butylN-[(3S)-1′-(5-bromo-3-carbamoylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(480 mg, 955 μmol) and TEA (197 μL, 1.43 mmol) in DCM (10.0 mL) wasadded TFFA (201 μL, 1.43 mmol) slowly at 0° C. The reaction mixture wasstirred at 0° C. for 15 min. Then the reaction mixture was quenched withH₂O (20.0 mL) and extracted with DCM (50.0 mL). The combined organiclayers were washed with brine (20.0 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by flash silica gel chromatography (12 g column,EtOAc in petroleum ether from 0% to 10%) to give tert-butylN-[(3S)-1′-(5-bromo-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(361 mg, 78% yield) as a light yellow oil. LC-MS (ESI+) m/z: 506.0(M+Na)⁺.

2-chloro-5-iodo-3-methyl-3,4-dihydropyrimidin-4-one, Intermediate DP

Step a:

To a solution of 2,4-dichloro-5-iodopyrimidine (3.5 g, 12.7 mmol, CAS#13544-44-0) in THE (60 ml) was added sodium hydroxide (1 N, 45 mL). Thereaction mixture was stirred at 15° C. for 12 hours. The mixture wasthen extracted with ethyl acetate (50 mL×1). The aqueous layer wasadjusted to pH=5-6 with aqueous HCl (2 N) and extracted with ethylacetate (50 mL×4). The combined organic layers were washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to givea residue. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:20 to 100:60) to afford2-chloro-5-iodo-3,4-dihydropyrimidin-4-one (620 mg, 19% yield) as ayellow solid. LC-MS (ESI+) m/z: 256.8 (M+H)⁺.

Step b:

To a solution of 2-chloro-5-iodo-3,4-dihydropyrimidin-4-one (400 mg,1.55 mmol) in DMF (10 mL) was added LDA (1.55 mL, 2.0 M in THF) dropwiseat 0° C. The mixture was stirred at 0° C. for 5 min, then Mel (212.0 tL, 3.41 mmol) was added. The mixture was allowed to warm up to 15° C.and stirred at this temperature for 18 h. The mixture was then dilutedwith H₂O (20 mL), and extracted with ethyl acetate (200 mL×3). Thecombined organic layers were washed with saturated NH₄Cl (60 mL×2),brine (100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedto give a residue. The residue was purified by flash silica gelchromatography (ethyl acetate/petroleum ether=0/100 to 30/100) to afford2-chloro-5-iodo-3-methyl-3,4-dihydropyrimidin-4-one (234.0 mg, 56%yield) as a white solid. LC-MS (ESI⁺) m/z: 270.7 (M+H)⁺.

(S)-tert-butyl(1′-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate DO

Step a:

2-Chloro-5-iodo-3-methyl-3,4-dihydropyrimidin-4-one (234.0 mg, 865 μmol,Intermediate DP), DIPEA (766 μL, 4.32 mmol), and(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine dihydrochloride (283mg, 1.03 mmol, Intermediate I) were placed into DMF (10 mL). Thereaction mixture was evacuated and refilled 3 times using N₂. Thereaction mixture was stirred at 100° C. for 2 hours. The mixture cooledto rt and was used in the next step without further purification. LC-MS(ESI⁺) m/z: 458.9 (M+H)⁺.

Step b:

A mixture of 2-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4 (377.0 mg, 864μmol), TEA (362 μL, 2.59 mmol) and (Boc)₂O (295 μL, 1.29 mmol) in DMF(10 mL) was stirred at 15° C. for 2 hours. The mixture was thenconcentrated and purified by flash silica gel chromatography (petroleumether:EtOAc=100:0 to 100:60) to afford (S)-tert-butyl(1′-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(150.0 mg, 32% yield) as a colorless oil. LC-MS (ESI+) m/z: 537.1(M+Na)⁺.

1-benzyl-6-chloro-3-iodo-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,Intermediate DR

Step a:

A mixture of1-benzyl-3-iodo-7-(4-methoxybenzyl)-5-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(1.0 g, 2.0 mmol, CAS #2055938-41-3, synthesis described in PCT Int.Appl. 2016203404) in TFA (10 mL) and TfOH (0.1 mL) was stirred at 70° C.for 15 hours. The mixture was then concentrated to give a residue whichwas triturated with saturated aqueous NH₄Cl (100 mL), then extractedwith EtOAc (100 mL×2). The combined organic layer was concentrated togive a residue which triturated with EtOAc (3 mL), where precipitateformed. The solid was collected by filtration to afford1-benzyl-3-iodo-5-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(600 mg, 79% yield) as a green solid. LC-MS (ESI⁺) m/z: 383.0 (M+H)⁺.

Step b:

1-benzyl-3-iodo-5-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-d]pyrimidine-4,6-dione(500 mg, 1.30 mmol) and DIPEA (681 μL, 3.90 mmol) were added in thePOCl₃ (5 mL). The mixture was stirred at 120° C. for 12 h. The reactionmixture was then concentrated to give a residue which was diluted withEtOAc (20 mL). The mixture was added slowly into an ice and sat. aq.NaHCO₃ (30 mL). The partitioned layers were separated and the aqueousphase was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byflash silica gel chromatography (ethyl acetate/petroleum ether=0/100 to30/100) to give1-benzyl-6-chloro-3-iodo-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(400 mg, 998 μmol) as a gray solid. LC-MS (ESI⁺) m/z: 401.2 (M+H)⁺.

(S)-tert-butyl(1′-(1-benzyl-3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate DS

Step a:

1-Benzyl-6-chloro-3-iodo-5-methyl-1H, 4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (210.0 mg, 524 μmol, Intermediate DR),(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(172.0 mg, 628 μmol, Intermediate I) and DIPEA (455 μL, 2.61 mmol) wereadded in DMSO (2.00 mL). The reaction mixture was stirred at 120° C. for12 hours. The reaction mixture was cooled to rt and the crude solutionwas used into the next step without further purification. LC-MS (ESI⁺)m/z: 550.0 (M−NH₂)⁺.

Step b:

The (Boc)₂O (178 μL, 783 μmol) was added into a mixture of(S)-6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1-benzyl-3-iodo-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(296.0 mg, 522 μmol) in DMSO (3 mL). The mixture was stirred at 30° C.for 2 hours. Then the mixture was diluted with EtOAc (30 mL). Themixture was washed with H₂O (20 mL×3), brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (ethylacetate/petroleum ether=0/100 to 50/100) to give (S)-tert-butyl(1′-(1-benzyl-3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(200.0 mg, 58% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 667.1 (M+H)⁺.

(R)—N—((S)-1′-(5-bromo-3,6-dimethylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide,Intermediate DT

Step a:

To a solution of(R)—N—((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(1.00 g, 3.76 mmol, synthesized via Step a of Example 120) in DMF (10.0mL) was added 2,5-dibromo-3,6-dimethylpyrazine (1.33 g 3.76 mmol, CAS#121594-49-8) and TEA (1.90 g, 18.8 mmol, 2.62 mL), and the resultingmixture was stirred at 80° C. for 12 hrs. The mixture was then dilutedwith H₂O (50 mL) and extracted with ethyl acetate 90 mL (30 mL×3). Thecombined organic layers were washed with brine (50 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=10/1 to 1/1) to give(R)—N—((S)-1′-(5-bromo-3,6-dimethylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(1.12 g, 2.07 mmol, 55% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 493.2(M+H)⁺; ¹HNMR (400 MHz, CDCl3): δ 7.33 (d, J=6.8 Hz 1H), 7.25-7.20 (m,3H), 4.58 (d, J=10 Hz, 1H), 3.66 (d, J=10 Hz 1H), 3.46-3.40 (m, 2H),3.15 (d, J=16 Hz 1H), 3.07-3.01 (m, 1H), 2.96-2.91 (m, 1H), 2.75 (d,J=16 Hz 1H), 2.50 (d, J=12.4 Hz 6H), 2.41-2.34 (m, 1H), 2.00-1.94 (m,1H), 1.67 (d, J=13.6 1H), 1.40-1.37 (m, 1H), 1.30 (s, 9H).

(R)—N—((S)-1′-(6-bromo-5-methylpyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide,Intermediate DU

Step a:

To a solution of 2-bromo-5-iodo-3-methylpyridine (500 mg, 167.8 umol,CAS #65550-78-9) in toluene (1.00 mL) was added(R)—N—((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(594.8 mg, 1.68 mmol, synthesized via Step a of Example 120), Cs₂CO₃(1.64 g, 5.03 mmol, 3.00 eq) and Xantphos-Pd-G4 (161.5 mg, 167.8 umol,0.10 eq), and the resulting mixture was stirred at 80° C. for 12 hrs.The mixture was then diluted with H₂O (20 mL), and the mixture wasextracted with ethyl acetate (20.0 mL×3). The organic extracts werecombined and washed with brine (50.0 mL), dried over Na₂SO₄, filteredand concentrated to give a yellow residue. The yellow residue waspurified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water(0.225% FA)-ACN]; B %: 55%-85%, 10 min) to give(R)—N—((S)-1′-(6-bromo-5-methylpyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(330 mg, 678 umol, 40% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 478.1(M+H)⁺; ¹HNMR (400 MHz, CDCl3) δ 7.87 (d, J=2.8 Hz, 1H), 7.34-7.32 (m,1H), 7.26-7.21 (m, 3H), 7.09 (d, J=2.8 Hz, 1H), 4.59 (d, J=10 Hz, 2H),3.62-3.50 (m, 3H), 3.1 (d, J=16 Hz, 1H), 2.98-2.87 (m, 2H), 2.75 (d,J=16 Hz, 1H), 2.43 (m, 1H), 2.33 (s, 3H), 2.01-1.94 (m, 1H), 1.72-1.71(m, 1H), 1.44-1.40 (m, 1H), 1.31 (s, 9H).

(R)—N—((S)-1′-(5-bromo-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide,Intermediate DV and(R)—N—((S)-1′-(5-chloro-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide,Intermediate DW

Step a:

To a solution of 2-bromo-5-chloro-3-methylpyrazine (400 mg, 1.93 mmol,CAS #1260664-82-1) in DMF (2.00 mL) was added(R)—N—((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(683.36 mg, 1.93 mmol, synthesized via Step a of Example 120) and TEA(975.53 mg, 9.64 mmol, 1.34 mL), and the mixture was stirred at 80° C.for 3 h. The mixture was then adjusted to pH to 6-7 with FA. The mixturewas then purified by pre-HPLC (column: Phenomenex Synergi Max-RP 150*50mm*10 μm; mobile phase: [water(0.225% FA)-ACN]; B %: 48%-78%, 10 min) togive(R)—N—((S)-1′-(5-bromo-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(290 mg, 607.38 μmol, 32% yield) as a white solid (LC-MS (ESI⁺) m/z:479.2 (M+H)⁺) and(R)—N—((S)-1′-(5-chloro-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(135 mg, 312 mol, 16% yield) as a white solid (LC-MS (ESI⁺) m/z: 433.2(M+H)⁺).

Tert-butyl(S)-(5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate DX

Step a:

To a solution of(S)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (3.00 g,10.2 mmol, Intermediate BX) in DMF (30.0 mL) was added NaOH (2.29 g,57.3 mmol). The mixture was stirred at 25° C. for 5 min, then to themixture was added Boc₂O (6.70 g, 30.7 mmol). The mixture was stirred at25° C. for 5 hr. The mixture was then poured into water (50.0 mL), andextracted with ethyl acetate (40.0 mL×3). The combined organic layer waswashed with brine (40.0 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by Pre-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 65%-90%,28min) to give tert-butyl(S)-1-((tert-butoxycarbonyl)amino)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(3.21 g, 7.59 mmol, 74% yield) as a white solid. LC-MS (ESI⁺) m/z: 421.2(M+H)⁺.

Step b:

To a solution of tert-butyl(S)-1-((tert-butoxycarbonyl)amino)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(3.21 g, 7.59 mmol) in DCM (30.0 mL) was added ZnBr₂ (3.42 g, 15.2 mmol,759 uL) and the mixture was stirred at 25° C. for 12 h. The mixture wasthen concentrated under reduced pressure to give the residue. Themixture was purified by Pre-HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 10%-25%, 13 min) togive tert-butyl(S)-(5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.5 g, 4.68 mmol, 62% yield) as a white oil. LC-MS (ESI⁺) m/z: 321.2(M+H)⁺.

Tert-butyl(S)-(1′-(6-bromopyridin-3-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate DY

Step a:

To a solution of 2-bromo-5-iodopyridine (1.33 g, 4.68 mmol), tert-butyl(S)-(5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.50 g, 4.68 mmol, Intermediate DX) and Cs₂CO₃ (4.58 g, 14.04 mmol) intoluene (15.0 mL) was added XantPhos-Pd-G4 (451 mg, 468 umol), and themixture was stirred at 80° C. for 12 h. The mixture was then filteredand the filtrate was concentrated under reduced pressure to give aresidue. The residue was purified by Pre-HPLC (column: Phenomenex GeminiC18 250*50 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 58%-83%, 28 min) to give tert-butyl(S)-(1′-(6-bromopyridin-3-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(645 mg, 1.34 mmol, 29% yield,) as a yellow solid. LC-MS (ESI⁺) m/z:478.3 (M+H)⁺.

Tert-butyl(S)-(5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate,Intermediate DZ

Step a:

To a solution of(S)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (2.00 g,6.82 mmol, Intermediate Y) in DMF (20.0 mL) was added Boc₂O (4.47 g,20.5 mmol, 4.70 mL) and NaOH (1.53 g, 38.2 mmol), and the mixture wasstirred at 25° C. for 5 h. The mixture was poured into water (40.0 mL),and extracted with ethyl acetate (30.0 mL×3). The combined organic layerwas washed with brine (30.0 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by Pre-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 64%-89%,28 min) to give tert-butyl(S)-1-((tert-butoxycarbonyl)amino)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.78 g, 4.23 mmol, 62% yield) as a white solid. LC-MS (ESI⁺) m/z: 421.1(M+H)⁺.

Step b:

To a solution of tert-butyl(S)-1-((tert-butoxycarbonyl)amino)-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.78 g, 4.23 mmol) in DCM (20.0 mL) was added ZnBr₂ (1.91 g, 8.47 mmol,424 uL), and the mixture was stirred at 25° C. for 12 h. The mixture wasconcentrated under reduced pressure to give the residue. The mixture waspurified by Pre-HPLC (column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water(0.225% FA)-ACN]; B %: 10%-25%, 13 min) to givetert-butyl(S)-(5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(1.1 g, 3.43 mmol, 81% yield) was obtained as a white oil. LC-MS (ESI⁺)m/z: 321.1 (M+H)⁺.

Tert-butyl(S)-(1′-(6-bromopyridin-3-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate EA

Step a:

To a solution of 2-bromo-5-iodopyridine (975 mg, 3.43 mmol), tert-butyl(S)-(5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(1.10 g, 3.43 mmol, Intermediate DZ) and Cs₂CO₃ (3.36 g, 10.3 mmol) intoluene (15.0 mL) was added XantPhos-Pd-G4 (330 mg, 343 umol). Themixture was stirred at 80° C. for 12 h. Then the mixture was filteredwith diatomaceous earth and the filtrate was concentrated under reducedpressure to give a residue. The mixture was purified by Pre-HPLC(column: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 57%-82%, 35 min) to givetert-butyl(S)-(1′-(6-bromopyridin-3-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(596 mg, 1.25 mmol, 36% yield) as a white solid. LC-MS (ESI⁺) m/z: 500.1(M+23)⁺; ¹HNMR (400 MHz, CDCl3): δ 8.04 (d, J=3.20 Hz, 1H), 7.31-7.14(m, 1H), 7.14-7.10 (m, 1H), 7.56-7.53 (m, 2H), 6.98-6.93 (m, 2H), 5.02(d, J=10.0 Hz, 1H), 4.68 (d, J=10.0 Hz, 1H), 3.57-3.50 (m, 2H),3.02-2.92 (m, 3H), 2.72 (d, J=15.6 Hz, 1H), 2.04-2.01 (m, 1H), 1.84-1.78(m, 2H), 1.49 (s, 9H), 1.44-1.40 (m, 1H).

Tert-butyl (R)-(3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamate,Intermediate EB

Step a:

Tert-butyl(R)-3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate,synthesized via Boc protection of(R)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine, Intermediate CB (understandard conditions with Boc₂O) was mono-deprotected using ZnBr₂, asdescribed in Step b of Intermediate DZ to give tert-butyl(R)-(3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamate.

(R)—N—((R)-1′-(6-bromopyridin-3-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide,Intermediate EC

Step a:

To a solution of 2-bromo-5-iodopyridine (1.00 g, 3.52 mmol), tert-butyl(R)-(3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamate (1.09 g, 3.52mmol, Intermediate EB) and Cs₂CO₃ (3.44 g, 10.6 mmol) in toluene (10.0mL) was added XantPhos-Pd-G4 (339 mg, 352 umol). The mixture was stirredat 80° C. for 12 h. The mixture was then filtered and the filtrate wasconcentrated under reduced pressure to give a residue. The residue waspurified by Pre-HPLC (column: Phenomenex Synergi C18 250*50*10 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 46%-71%,36 min, 80% min) to give(R)—N—((R)-1′-(6-bromopyridin-3-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfinamide(570 mg, 1.23 mmol, 35% yield) as a white solid. LC-MS (ESI⁺) m/z: 466.1(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.04 (d, J=3.20 Hz, 1H), 7.31-7.29 (m,3H), 7.14-7.11 (m, 1H), 7.56-7.53 (m, 2H), 6.96-6.95 (m, 1H), 6.85 (d,J=8.00 Hz, 1H), 4.73 (d, J=10.8 Hz, 1H), 3.72 (d, J=10.8 Hz, 1H),3.66-3.53 (m, 2H), 3.26-3.22 (m, 2H), 2.28-2.16 (m, 1H), 2.16-2.13 (m,1H), 1.96-1.83 (m, 2H), 1.28 (s, 9H).

Ethyl(S)-3-((5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate,Intermediate ED

Step a:

To a mixture of 2-bromo-5-chloropyrazine (46.0 g, 237 mmol) and ethyl3-mercaptopropanoate (31.9 g, 237 mmol) in dioxane (460 mL) was addedDIPEA (61.4 g, 475 mmol, 82.8 mL), Xantphos (13.7 g, 23.8 mmol) andPd₂(dba)₃ (10.8 g, 11.8 mmol) in one portion under N₂. The mixture wasstirred at 80° C. for 2 hours under N₂. The mixture was then filteredand the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ethyl acetate=1:0 to 5:1,petroleum ether:ethyl acetate=10:1) to afford ethyl3-((5-chloropyrazin-2-yl)thio)propanoate (52.0 g, 192 mmol, 81% yield)as a light yellow oil. LC-MS (ESI⁺) m/z: 247.1 (M+H)⁺; ¹HNMR (400 MHz,CDCl₃): δ 8.37 (s, 1H), 8.20 (s, 1H), 4.18-4.13 (m, 2H), 3.40 (t, J=7.0Hz, 2H), 2.73 (t, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).

Step b:

To a solution of ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate (18.0 g,72.9 mmol) and (S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine,(20.1 g, 72.9 mmol, Intermediate I, 2HCl) in NMP (180 mL) was addedNa₂CO₃ (30.9 g, 291 mmol) at 25° C. Then the mixture was heated to 130°C. and stirred for 1 h. The mixture was then cooled to 25° C. To thereaction mixture was next added (Boc)₂O (7.00 g, 32.1 mmol, 7.37 mL) andDIPEA (4.15 g, 32.1 mmol, 5.59 mL) and the mixture was stirred at 25° C.for 1 h. Then to the mixture was added additional (Boc)₂O (10.5 g, 48.2mmol, 11.1 mL) and DIPEA (5.28 g, 40.9 mmol, 7.12 mL) at 25° C. and themixture was stirred for another 1 h. The reaction mixture was thenpoured into water (600 mL) where precipitate formed, and the mixture wasextracted with EtOAc (200 mL×2). The combined organic layer was washedwith 0.500 N HCl (250 mL×2), brine (200 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica gel (eluted with petroleum ether:ethyl acetate=1:0 to 3:1) toafford ethyl(S)-3-((5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(7.50 g, 14.3 mmol, 20% yield) as yellow oil. LC-MS (ESI⁺) m/z: 513.3(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.071 (d, J=2.80 Hz, 2H), 7.29-7.27(m, 1H), 7.25-7.20 (m, 3H), 5.01 (d, J=10.0 Hz, 1H), 4.67 (s, 1H),4.18-4.11 (m, 4H), 3.29-3.26 (m, 2H), 3.19-3.16 (m, 2H), 3.05 (d, J=16.0Hz 1H), 2.79 (d, J=15.6 Hz 1H), 2.69-2.65 (m, 2H), 1.94-1.93 (m, 1H),1.74-1.71 (m, 2H), 1.46 (s, 9H), 1.28-1.24 (m, 3H).

8-(((5-bromopyrazin-2-yl)oxy)methyl)quinoline, Intermediate EE

Step a:

To a solution of quinolin-8-ylmethanol (1.70 g, 10.7 mmol) in DMF (65.0mL) was added NaH (428 mg, 10.7 mmol, 60% dispersion in mineral oil) at0° C. Then the mixture was stirred at 0° C. for 1 h. Next,2,5-dibromopyrazine (2.12 g, 8.91 mmol) was added to the mixture. Thenthe reaction mixture was stirred at 0 to 25° C. for 6 h. The mixture wasthen poured into water (200 mL) and extracted with ethyl acetate (150mL×3). The organic layer was washed with brine (100 mL×2), dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=1/0˜10/1,R_(f)=0.40) to give 8-(((5-bromopyrazin-2-yl)oxy)methyl)quinoline (1.80g, 5.68 mmol, 64% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 318.0(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.98-8.97 (m, 1H), 8.24-8.14 (m, 3H),7.87-7.82 (m, 2H), 7.57 (t, J=7.6 Hz, 1H), 7.48-7.45 (m, 1H), 6.13 (s,2H).

Tert-butyl (S)-(1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate EF

Step a:

To a solution of (S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(3.00 g, 10.9 mmol, Intermediate I, 2HCl) in DMF (30.0 mL) was addedNaOH (2.44 g, 61.0 mmol). The mixture was stirred at 25° C. for 5 min,then to the mixture was added Boc₂O (7.14 g, 32.7 mmol, 7.51 mL). Themixture was stirred at 25° C. for another 16 h. The mixture was thenpoured into water (100 mL) and extracted with ethyl acetate (50.0 mL×3).The combined organic layer was washed with saturated NH₄Cl solution(50.0 mL×2), brine (50.0 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give tert-butyl(S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(5.07 g, quant. crude yield) as a white solid. LC-MS (ESI⁺) m/z: 495.4(M−172)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.25-7.19 (m, 4H), 4.96 (br d,J=10.0 Hz, 1H), 4.63 (br d, J=9.2 Hz, 1H), 3.93 (br d, J=12.4 Hz, 2H),3.05-2.96 (m, 3H), 2.73 (br d, J=15.6 Hz, 1H), 1.83-1.76 (m, 1H),1.63-1.59 (m, 3H), 1.49-1.47 (m, 18H).

Step b:

To a solution of tert-butyl(S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(4.00 g, 9.94 mmol) in DCM (40.0 mL) was added ZnBr₂ (4.48 g, 19.9 mmol,995 uL) and the mixture was stirred at 25° C. for 12 h. Then, additionalZnBr₂ (2.24 g, 9.94 mmol, 497 uL) was added to the mixture and themixture was stirred at 25° C. for another 4 h. The mixture was thenconcentrated under reduced pressure to remove DCM. The residue wasdissolved with MeOH (50.0 mL) and adjusted pH to 8˜9 with ammoniumhydroxide (25.0 mL, 28% solution). The mixture was then filtered and thefiltrate was concentrated to give a residue. The residue was purified byreversed-phase HPLC (FA condition) to give tert-butyl(S)-(1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate (1.50 g, 50%yield) as a red solid. LC-MS (ESI⁺) m/z: 303.2 (M+H)⁺; ¹HNMR (400 MHz,CDCl₃): δ 7.24-7.19 (m, 4H), 4.95 (br d, J=9.6 Hz, 1H), 4.71 (br d,J=10.0 Hz, 1H), 4.33 (br s, 2H), 3.14-2.87 (m, 5H), 2.73 (br d, J=15.6Hz, 1H), 1.91-1.84 (m, 1H), 1.69 (br d, J=14.0 Hz, 1H), 1.49 (s, 9H),1.35 (br d, J=14.0 Hz, 1H).

(3R)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-amine,Intermediate EG

Step a:

Boron trifluoride-Et₂O (103 mL, 402 mmol, 48% solution) was addeddropwise to a solution of 2-fluorobenzaldehyde (200 g, 168 mL, 1.61 mol)and propane-1,3-dithiol (176 g, 163 mL, 1.63 mol) in DCM (1.00 L) at 0°C. The reaction was then stirred at 25° C. for 1 h. The reaction mixturewas then poured into water (200 mL) and the organic phase was separatedand the aqueous phase was extracted with dichloromethane (200 mL×2). Thecombined organic fractions were washed with brine (200 mL), dried overanhydrous Na₂SO₄, then filtered and evaporated under reduced pressure.The crude product was triturated with petroleum ether (1.00 L) at 25° C.for 1 h, and then filtered. The residue was dried in vacuo to give2-(2-fluorophenyl)-1,3-dithiane (302 g, 1.40 mol, 87% yield) as a whitesolid. ¹HNMR (400 MHz, CDCl₃): δ 7.64-7.62 (m, 1H), 7.31-7.25 (m, 1H),7.18-7.16 (m, 1H), 7.08-7.06 (m, 1H), 5.57 (s, 1H), 3.15-3.09 (m, 2H),2.94-2.90 (m, 2H), 2.20-2.16 (m, 1H), 1.97-1.93 (m, 2H).

Step b:

A mixture of 2-(2-fluorophenyl)-1,3-dithiane (100 g, 464 mmol) in THE(500 mL) was cooled to −50˜−40° C. for 30 min with stirring under N₂atmosphere. To the mixture was added LDA (2.00 M, 278 mL) dropwise at−50-40° C. for 30 min. Then the mixture was warmed to −30˜−20° C. for 1hr. Next the mixture was cooled to −50˜−40° C. again and to the mixturewas added a solution of tert-butyl(1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (109 g, 487 mmol,CAS #185099-67-6) dropwise in THE (200 mL) for 1 hr. After addition, themixture was stirred at −50˜−40° C. for another 1 hr. The mixture waswarmed to 0° C. and it was quenched with sat. NH₄Cl (500 mL) at 25° C.and extracted with ethyl acetate (500 mL×2) at 25° C. The organic phasewas dried with Na₂SO₄, filtered and the filtrate was concentrated invacuo to give a crude product. The crude product was triturated withpetroleum ether (500 mL) at 25° C. for 1 hr, and then filtered. Theresidue was dried in vacuo to give tert-butyl(1R,3r,5S)-3-(2-(2-fluorophenyl)-1,3-dithian-2-yl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate(182 g, 414 mmol, 89% yield) as a white solid. LC-MS (ESI⁺) m/z: 340.1(M−99)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.03 (t, J=7.6 Hz, 1H), 7.32-7.31 (m,1H), 7.18 (t, J=7.2 Hz, 1H), 7.10-7.05 (m, 1H), 4.21 (s, 1H), 4.13 (s,1H), 2.82-2.76 (m, 2H), 2.62-2.55 (m, 4H), 2.42 (s, 1H), 2.06-2.01 (m,2H), 1.84-1.81 (m, 4H), 1.89-1.55 (m, 1H), 1.46 (s, 9H).

Step c:

A mixture of tert-butyl(1R,3r,5S)-3-(2-(2-fluorophenyl)-1,3-dithian-2-yl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate(180 g, 409 mmol), Pyridine (66.1 mL, 818. mmol), Py.HBr₃ (26.4 g, 81.8mmol) in water (90.0 mL) and DCM (900 mL) was added TBAB (261 g, 818mmol) at 0° C. The mixture was stirred at 25° C. for 2 hrs. The reactionmixture was then poured into water (2.00 L) and extracted with DCM (1.00L×3). The combined organic layers were washed with brine (1.00 L), driedover anhydrous Na₂SO₄, then filtered and evaporated under reducedpressure to give a residue. Tert-butyl(1R,3r,5S)-3-(2-fluorobenzoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate(140 g, 98% crude yield) was obtained as a yellow gum and was used intothe next step without further purification.

Step d:

A mixture of tert-butyl(1R,3r,5S)-3-(2-fluorobenzoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate(140 g, 400 mmol) in dioxane (700 mL) was added t-BuOK (67.4 g, 601mmol) at 20° C. The mixture was then stirred at 70° C. for 2 hrs. Thereaction mixture was poured into water (1.50 L) and extracted with ethylacetate (1.00 L×2). The combined organic layers were washed with brine(1.00 L), dried over anhydrous Na₂SO₄, then filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 20/1) togive tert-butyl(1′R,2r,5′S)-3-oxo-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octane]-8′-carboxylate(45.0 g, 135 mmol, 34% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 352.1(M+Na)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.63 (t, J=8 Hz, 2H), 7.12-7.00 (m,2H), 4.40-4.29 (m, 2H), 2.33-2.23 (m, 4H), 2.04 (d, J=4.8 Hz, 2H), 1.55(d, J=13.6 Hz, 2H), 1.51 (s, 9H).

Step e:

To a solution of tert-butyl(1′R,2r,5′S)-3-oxo-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octane]-8′-carboxylate(45.0 g, 135 mmol) in 2-Me-THF (90.0 mL) were added Ti(OEt)₄ (92.7 g,406 mmol, 84.3 mL) and (R)-2-methylpropane-2-sulfinamide (32.8 g, 271mmol) at 25° C. Then the mixture was stirred at 90° C. for 96 hrs. Thereaction mixture was then cooled to −5˜0° C., and LiBH4 (3.25 g, 149mmol, 1.10 eq) was added carefully portionwise keeping the temperatureat −5˜0° C. over 1 hr, then the mixture was stirred at −5˜0° C. for 2hours. The solution was quenched by addition methanol (2.00 mL) at 0˜10°C. and2-[2-[bis(2-hydroxyethyl)amino]ethyl-(2-hydroxyethyl)amino]ethanol (50.0g) was added, and the mixture was stirred for 1 hr at 20° C. Then, tothe mixture was added 0.5 N HCl to adjust the pH=1.00, and the mixturewas extracted with ethyl acetate (2.00 L×3). The combined organic layerswere washed with brine (1.00 L), dried over anhydrous Na₂SO₄, thenfiltered through SiO₂ using petroleum ether/ethyl acetate=1:1 (2 L×3)and evaporated under reduced pressure. Then, to the crude residue wasadded methyl tert-butyl ether (100 mL) and the mixture was stirred at20° C. for 2 hrs, then filtered and the cake was dried to givetert-butyl(1′R,2r,3R,5′S)-3-(((R)-tert-butylsulfinyl)amino)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octane]-8′-carboxylate(28.0 g, 64.1 mmol, 47% yield) as a white solid. LC-MS (ESI⁺) m/z: 335.0(M−99)⁺; ¹HNMR (400 MHz, DMSO): δ 7.27 (d, J=7.6 Hz, 1H), 7.20 (t, J=7.2Hz, 1H), 6.91-6.87 (m, 1H), 6.80 (d, J=8 Hz, 1H), 6.03 (d, J=10 Hz, 1H),4.47 (d, J=10 Hz, 1H), 4.21 (s, 1H), 4.14 (s, 1H), 2.33-2.31 (m, 1H),2.16 (d, J=7.2 Hz, 2H), 1.97-1.76 (m, 5H), 1.43 (s, 9H), 1.15 (s, 9H).

Step f:

To a solution of tert-butyl(1′R,2r,3R,5′S)-3-(((R)-tert-butylsulfinyl)amino)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octane]-8′-carboxylate(10.0 g, 22.9 mmol) in MeOH (20.0 mL) was added HCl/MeOH (4.00 M, 50.0mL). The mixture was stirred at 20° C. for 2 hrs. The reaction mixturewas concentrated under reduced pressure to remove methanol to give aresidue. The residue was triturated with ethyl acetate (50.0 mL) at 20°C. for 30 min. Then the mixture was filtered and the filtrate cake wasconcentrated under reduced pressure to give(1′R,2r,3R,5′S)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-amine(6.5 g, 21.4 mmol, 94% yield, 2HCl) as a white solid. LC-MS (ESI⁺) m/z:231.1 (M+H)⁺; ¹HNMR (400 MHz, DMSO): δ 9.74 (s, 1H), 9.36 (s, 1H), 8.98(s, 3H), 7.71 (d, J=7.6 Hz, 1H), 7.36-7.33 (m, 1H), 7.02-6.95 (m, 2H),4.53 (s, 1H), 4.19 (s, 1H), 4.00 (s, 1H), 3.16 (s, 2H), 2.82-2.77 (m,1H), 2.41-2.40 (m, 1H), 2.27-2.23 (m, 2H), 2.14-2.02 (m, 3H), 1.87 (d,J=15.2 Hz, 1H).

3-chloro-4-((5-chloropyrazin-2-yl)thio)pyridin-2-amine, Intermediate EH

Step a:

To a solution of 2-bromo-5-chloropyrazine (20.0 g, 103 mmol) and sodium2-amino-3-chloropyridine-4-thiolate (18.9 g 103 mmol, Intermediate AC)in dioxane (80.0 mL) was added Pd₂(dba)₃ (3.79 g, 4.14 mmol), Xantphos(2.99 g, 5.17 mmol) and DIPEA (26.7 g, 207 mmol, 36.0 mL) at 25° C. Thenthe mixture was heated to 80° C. and stirred at 80° C. for 3 h. Themixture was then cooled to 25° C. and filtered. The filter cake waswashed with ethyl acetate (50.0 mL×3). The combined organic layer wasconcentrated to give a residue. The residue was purified by columnchromatography twice (SiO₂, petroleum ether:ethyl acetate=20:1 to 3:1,TLC: petroleum ether:ethyl acetate=3:1, R_(f)=0.25) to afford3-chloro-4-((5-chloropyrazin-2-yl)thio)pyridin-2-amine (3.00 g, 10.4mmol, 10% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 273.0 (M+H)⁺;¹HNMR (400 MHz, CDCl₃): δ 8.50 (d, J=1.2 Hz, 1H), 8.34 (d, J=1.2 Hz,1H), 7.87 (d, J=4.0 Hz, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.52 (s, 2H).

Ethyl 3-chloro-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate,Intermediate EI

Step a:

To a solution of ethyl 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate(1.00 g, 3.58 mmol, CAS #2091009-80-0) and K₂CO₃ (494 mg, 3.58 mmol) inACN (10.0 mL) and H₂O (2.00 mL) was added (2,3-dichlorophenyl)boronicacid (887 mg, 4.65 mmol) and Pd(dppf)Cl₂ (262 mg, 358 umol) at 25° C.The solution was heated to 80° C. and stirred for 2 h. The reactionmixture was then quenched by addition water (20.0 mL) and extracted withethyl acetate (20.0 mL×3). The combined organic layers were washed withsaturated NaCl (20.0 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give red oil. The residue was purified bysilica gel chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to0/1) to give ethyl3-chloro-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate (683 mg,1.98 mmol, 55% yield) as a white solid. LC-MS (ESI⁺) m/z: 345.0/347.0(M+H)⁺.

2-Chloro-N,6-dimethylisonicotinamide, Intermediate EJ

Step a:

To the stirred solution of 2-chloro-6-methylisonicotinic acid (500 mg,2.91 mmol, CAS #25462-85-5), methanamine hydrochloride (984 mg, 14.6mmol) and TEA (2.03 mL, 14.6 mmol,) in DMF (20.0 mL) was added HATU(2.22 g, 5.83 mmol). The reaction mixture was stirred at 15° C. for 2 h.The reaction mixture was then poured into H₂O (50.0 mL) and extractedwith ethyl acetate (30.0 mL×3). The combined organic layers were washedwith brine (30.0 mL×3), dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography (petroleum ether/ethylacetate=50/1-2/1, R_(f)=0.35) to give2-chloro-N,6-dimethylisonicotinamide (900 mg, crude) as a yellow oil.LC-MS (ESI⁺) m/z: 185.0 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.44 (s, 1H),7.41 (s, 1H), 6.37 (br s, 1H), 3.02 (d, J=4.4 Hz, 3H), 2.59 (s, 3H).

Tert-butyl(S)-(1′-(4-iodo-3-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate EK

Step a:

To the stirred solution of 2-fluoro-4-iodo-3-methylpyridine (1.00 g,4.22 mmol, CAS #153034-80-1) and DIPEA (2.94 mL, 16.9 mmol) in NMP (5.00mL) was added (S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (1.39g, 5.06 mmol, 2HCl, Intermediate I) at 20° C. The mixture was stirred at120° C. for 14 h. Then more DIPEA (2.00 mL) was added and the reactionmixture was stirred at 130° C. for 14 h. Next, Boc₂O (1.38 g, 6.33 mmol,1.45 mL) was added at 15° C. and the reaction mixture was stirred at 15°C. for 4 h. The reaction mixture was then diluted with H₂O (20.0 mL) andextracted with ethyl acetate (30.0 mL×3). The combined organic layerswere washed with brine (20.0 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (petroleum ether/ethylacetate=1/0-5/1, R_(f)=0.50) to give the crude product (600 mg) as alight yellow oil. The oil was purified by reverse MPLC (FA condition) togive tert-butyl(S)-(1′-(4-iodo-3-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(110 mg, 212 umol, 5% yield) as a yellow gum. LC-MS (ESI⁺) m/z: 520.1(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.73 (d, J=5.2 Hz, 1H), 7.39 (d, J=5.2Hz, 1H), 7.31-7.29 (m, 1H), 7.24-7.20 (m, 3H), 5.01 (d, J=10.0 Hz, 1H),4.68 (d, J=10.4 Hz, 1H), 3.31 (d, J=10.8 Hz, 2H), 3.07-2.90 (m, 4H),2.80 (d, J=16.0 Hz, 1H), 2.41 (s, 3H), 2.12-2.07 (m, 1H), 1.86-1.80 (m,1H), 1.73-1.67 (m, 1H), 1.51 (s, 9H).

Tert-butyl(S)-(1′-(4-iodo-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate EL

Step a:

To a solution of 2-fluoro-4-iodo-6-methylpyridine (800 mg, 3.38 mmol,CAS #884494-45-5) and(S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (1.11 g, 4.05 mmol,Intermediate I, 2HCl) in NMP (10.0 mL) was added DIPEA (2.35 mL, 13.50mmol) at 25° C., then the mixture was stirred at 120° C. for 24 h. Then,additional (S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine (464 mg,1.69 mmol, Intermediate I, 2HCl) and DIPEA (1.18 mL, 6.75 mmol) wereadded with stirring at 120° C. for 3 h. Next, (Boc)₂O (1.10 g, 5.06mmol, 1.16 mL) was added to the mixture with stirring, then the reactionwas stirred at 25° C. for 12 h. The reaction mixture was poured intowater (100 mL), and then the aqueous phase was extracted with ethylacetate (100 mL×2). The combined organic phase was washed with brine(100 mL×3), dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by column chromatography (100-200 mesh silicagel, petroleum ether/ethyl acetate=100/1 to 20/1, Product R_(f)=0.48) toafford tert-butyl(S)-(1′-(4-iodo-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(860 mg, 49% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 520.1 (M+H)⁺.

Tert-butyl(S)-(1′-(3-bromo-5-methylphenyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate EM

Step a:

To a solution of 1,3-dibromo-5-methylbenzene (450 mg, 1.80 mmol, CAS#1611-92-3), tert-butyl(S)-(1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate (327 mg,1.08 mmol, Intermediate EF) and Cs₂CO₃ (1.76 g, 5.40 mmol) in dioxane (2mL) was added Xantphos (208 mg, 360 umol) and Pd₂(dba)₃ (165 mg, 180umol) under N₂, then the mixture was stirred at 100° C. for 4 h. Thereaction mixture was poured into water (100 mL), then the aqueous phasewas extracted with ethyl acetate (100 mL×2). The combined organic phasewas washed with brine (100 mL×2), dried over Na₂SO₄, filtered andconcentrated in vacuo to give a crude product, which was purified bysilica gel chromatography (100-200 mesh silica gel, petroleumether/ethyl acetate=100/1 to 5/1, R_(f)=0.45) to afford tert-butyl(S)-(1′-(3-bromo-5-methylphenyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(180 mg, 35% yield) as yellow oil. LC-MS (ESI⁺) m/z: 471.1 (M+H)⁺; ¹HNMR(400 MHz, CDCl₃): δ 7.63-7.65 (m, 2H), 7.53-7.58 (m, 2H), 7.12 (s, 1H),7.08 (s, 1H), 6.86-6.88 (m, 1H), 3.72 (s, 3H), 3.51-3.54 (m, 1H), 3.02(s, 3H), 2.88-2.90 (m, 2H), 2.72-2.74 (m, 2H), 2.27-2.30 (m, 4H),1.27-1.55 (m, 9H).

6-Chloro-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine,Intermediate EN

Step a:

To a mixture of 3,6-dichloro-4-(trifluoromethyl)pyridazine (4.50 g, 20.7mmol, CAS #1057672-68-0) in EtOH (45.0 mL) was added TEA (3.18 mL, 22.8mmol) and NH₂NH₂.H₂O (4.86 g, 97.1 mmol, 4.72 mL), and the mixture wasstirred at 85° C. for 3 h. The mixture was concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC (FAcondition) to give 6-chloro-3-hydrazineyl-4-(trifluoromethyl)pyridazine(1.10 g, 5.18 mmol, 25% yield) as a brown solid. LC-MS (ESI⁺) m/z: 213.1(M+H)⁺; ¹HNMR (400 MHz, MeOD): δ 7.75 (s, 1H).

Step b:

To a solution of 6-chloro-3-hydrazineyl-4-(trifluoromethyl)pyridazine(1.10 g, 5.18 mmol, FA) in HCOOH (11.0 mL), and the mixture was stirredat 100° C. for 3 h. The mixture was concentrated under reduced pressureto remove HCOOH, then the residue was poured into aqueous NaHCO₃ (30.0mL) and extracted with ethyl acetate (20.0 mL×3). The combined organiclayers were washed with brine (30.0 mL), and concentrated under reducedpressure to give6-chloro-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (950 mg,4.27 mmol, 83% yield) as a brown solid. LC-MS (ESI⁺) m/z: 223.0 (M+H)⁺;¹HNMR (400 MHz, MeOD): δ 9.59 (s, 1H), 7.94 (s, 1H).

6-Bromo-8-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine, IntermediateEO

Step a:

To a mixture of 5-bromo-3-iodopyridin-2-amine (10.0 g, 33.5 mmol, CAS#381233-96-1) and 2-bromo-1,1-diethoxyethane (7.91 g, 40.1 mmol, 6.04mL) in EtOH (100 mL) was added HCl (10.0 M, 20.0 mL), and the reactionmixture was stirred at 75° C. for 16 h. The reaction mixture wasconcentrated under reduced pressure to remove EtOH, the residue wasdiluted with H₂O (200 mL) and the mixture was adjusted to pH=9 withaqueous NaHCO₃. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=10/1 to 1/1, R_(f)=0.21) to give6-bromo-8-iodoimidazo[1,2-a]pyridine (3.40 g, 10.5 mmol, 32% yield) as ayellow solid. LC-MS (ESI⁺) m/z: 322.9 (M+H)⁺; ¹HNMR (400 MHz, MeOD): δ8.72 (d, J=1.6 Hz, 1H), 7.98-7.97 (d, J=1.2 Hz, 1H), 7.88 (s, 1H), 7.61(d, J=1.2 Hz, 1H).

Step b:

A mixture of 6-bromo-8-iodoimidazo[1,2-a]pyridine (1.20 g, 3.72 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(773 mg, 3.72 mmol, CAS #847818-74-0), K₂CO₃ (770 mg, 5.57 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (607 mg, 743 umol) in H₂O (1.20 mL) and 1,4-dioxane(12.0 mL) was de-gassed and then heated to 60° C. for 16 h under N₂. Themixture was diluted with H₂O (100 mL) and extracted with ethyl acetate(100 mL×2), the combined organic layers were washed with brine (150 mL),concentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO2, petroleum ether/ethylacetate=10/1 to 1/1, R_(f)=0.30) to give6-bromo-8-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine (0.70 g, 2.53mmol, 68% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 277.1 (M+H)⁺;¹HNMR (400 MHz, MeOD): δ 8.86-8.85 (d, J=1.6 Hz, 1H), 7.96 (s, 1H), 7.63(d, J=1.2 Hz 1H), 7.60-7.59 (d, J=2.0 Hz, 1H), 7.48 (d, J=2.0 Hz 1H),6.57 (d, J=2.0 Hz 1H), 3.82 (s, 3H).

6-Bromo-8-(difluoromethoxy)imidazo[1,2-a]pyridine, Intermediate EP

Step a:

To a mixture of 2-amino-5-bromopyridin-3-ol (5.00 g, 23.5 mmol, CAS#39903-01-0) in DME (50.0 mL) was added NaOH (3.00 g, 75.0 mmol) in H₂O(30.0 mL) dropwise at 10˜20° C. The reaction mixture was degassed undervacuum and chloro(difluoro)methane (15.0 psi) was passed through thereaction mixture at 10˜20° C. and the mixture was stirred for 16 h. Thereaction mixture poured into H₂O (100 mL), then extracted with ethylacetate (50.0 mL×4). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, and concentrated under reduce pressure toget a residue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=1/0 to 0/1) to give5-bromo-3-(difluoromethoxy)pyridin-2-amine (1.70 g, 6.20 mmol, 26%yield) as a yellow solid. LC-MS (ESI⁺) m/z: 238.7 (M+H)⁺.

Step b:

To a mixture of 5-bromo-3-(difluoromethoxy)pyridin-2-amine (1.00 g, 4.18mmol) in EtOH (10.0 mL) was added 2-bromo-1,1-diethoxyethane (1.07 g,5.44 mmol, 818 uL) and HBr (7.45 g, 30.4 mmol, 5.00 mL, 33% in HOAc),and the mixture was stirred at 90° C. for 16 h. The mixture wasconcentrated under reduced pressure to remove EtOH, and the residue wasdissolved into ethyl acetate (50.0 mL) and washed with NaHCO₃ (50 mL)and brine (50.0 mL). The organic layer was dried with Na₂SO₄, thenconcentrated under reduced pressure to give6-bromo-8-(difluoromethoxy)imidazo[1,2-a]pyridine (900 mg, 3.42 mmol,82% yield) as a brown solid. LC-MS (ESI⁺) m/z: 265.1 (M+H)⁺; ¹HNMR (400MHz, MeOD): δ 8.67 (s, 1H), 7.98 (d, 1H), 7.67 (s, 1H), 7.29 (s, 1H),7.46-7.10 (m, 1H).

Tert-butyl(S)-(1′-(6-bromopyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate EQ

Step a:

A mixture of tert-butyl(S)-(1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate (1.00 g,3.31 mmol, Intermediate EF), 2-bromo-5-iodopyridine (1.03 g, 3.64 mmol),Cs₂CO₃ (3.23 g, 9.92 mmol), Pd₂(dba)₃ (303 mg, 331 umol) and RuPhos (308mg, 661 umol) in DMSO (20.0 mL) was degassed and purged with N₂ threetimes, and then the mixture was stirred at 100° C. for 3.5 h under N₂atmosphere. The reaction was poured into H₂O, then filtered and thefilter cake was collected. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to 0:1,R_(f)=0.45) to give tert-butyl(S)-(1′-(6-bromopyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(740 mg, 49% yield) as an orange solid. LC-MS (ESI⁺) m/z: 458.2 (M+H)⁺;¹HNMR (400 MHz, CDCl₃): δ 8.04 (d, J=3.2 Hz, 2H), 7.33-7.28 (m, 2H),7.25-7.19 (m, 3H), 7.12-7.09 (m, 1H), 5.02 (d, J=10 Hz, 1H), 4.66 (d,J=9.6 Hz, 1H), 3.58-3.50 (m, 2H), 3.04-2.93 (m, 3H), 2.76 (d, J=15.6 Hz,1H), 2.08-2.01 (m, 1H), 1.86-1.75 (m, 2H), 1.49 (s, 9H).

Sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridine-2-thiolate,Intermediate ER

Step a:

A mixture of tert-butyl(S)-(1′-(6-bromopyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(900 mg, 1.96 mmol, Intermediate EQ), ethyl 3-mercaptopropanoate (316mg, 2.36 mmol), Pd₂ (dba)₃ (89.9 mg, 98.1 umol), Xantphos (113 mg, 196umol), DIPEA (761 mg, 5.89 mmol, 1.03 mL) and dioxane (10.0 mL) wasstirred at 80° C. for 2 h under N₂. The mixture was then filtered andthe solution was concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, petroleum ether:ethyl acetate=10:1 to 3:1,R_(f)=0.3) to give ethyl(S)-3-((5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridin-2-yl)thio)propanoate(1.10 g, 1.83 mmol, 93% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 512.2(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.29-7.23 (m, 4H),7.21-7.11 (m, 2H), 5.02 (d, J=10 Hz, 1H), 4.66 (d, J=9.6 Hz, 1H),4.19-4.13 (m, 2H), 3.74-3.54 (m, 2H), 3.39-3.60 (m, 2H), 3.00-2.77 (m,3H), 2.75-2.71 (m, 3H), 2.05 (s, 1H), 1.87-1.84 (m, 2H), 1.57 (s, 9H),1.49-1.24 (m, 3H).

Step b:

To a solution of(S)-3-((5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridin-2-yl)thio)propanoate(0.50 g, 977 umol) in THE (5.00 mL) was added the solution of EtONa(99.7 mg, 1.47 mmol) in EtOH (1.00 mL) at 0° C. The mixture was stirredat 0° C. for 0.5 h, then warmed to 25° C. and stirred at 25° C. for 2 h.The mixture was then concentrated under vacuum to give sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridine-2-thiolate(423 mg, quant. crude yield) as a red solid. LC-MS (ESI⁺) m/z: 412.2(M−23+2H)⁺.

Sodium(R)-5-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate,Intermediate ES

Step a:

To a solution of ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate (2.00 g,8.11 mmol, synthesized via Step a of Intermediate ED) and(R)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine dihydrochloride (2.25 g,8.11 mmol, Intermediate CB) in NMP (20.0 mL) was added Na₂CO₃ (3.44 g,32.4 mmol) at 25° C. Then the mixture was heated to 130° C. and stirredat 130° C. for 1 h. Next, the mixture was cooled to 25° C. and Boc₂O(1.95 g, 8.92 mmol, 2.05 mL) and DIPEA (1.15 g, 8.92 mmol, 1.55 mL) wereadded and the mixture was stirred at 25° C. for 12 h. Then the mixturewas poured into water (100 mL), and extracted with ethyl acetate (100mL×2). The combined organic layer was washed with 0.5 N HCl solution(50.0 mL), saturated NaHCO₃ solution (50.0 mL), brine (50.0 mL), thendried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0˜3/1,Product R_(f)=0.40) to give ethyl(R)-3-((5-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(600 mg, 1.15 mmol, 14% yield) as yellow oil. LC-MS (ESI⁺) m/z: 515.2(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.09 (d, J=10.8 Hz, 2H), 7.32 (d,J=7.6 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 6.83 (d,J=8.0 Hz, 1H), 5.02 (d, J=8.8 Hz, 1H), 4.71 (d, J=8.8 Hz, 1H), 4.22-4.16(m, 1H), 4.13-4.08 (m, 2H), 3.47-3.42 (m, 2H), 3.28 (t, J=7.2 Hz, 2H),2.69 (t, J=7.2 Hz, 2H), 1.97-1.92 (m, 4H), 1.45 (s, 9H), 1.40 (s, 1H),1.27 (t, J=7.2 Hz, 3H).

Step b:

To a solution of ethyl(R)-3-((5-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(350 mg, 680 umol) in THF (5.00 mL) was added a solution of EtONa (69.4mg, 1.02 mmol, 8.52 uL) in EtOH (1.00 mL) at 0° C. Then the mixture wasstirred at 0° C. for 0.5 h and was allowed to warm to 25° C. and stirredfor 1.5 h. The mixture was concentrated under vacuum to give sodium(R)-5-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate(290 mg, quant. crude yield) as a yellow solid. LC-MS (ESI⁺) m/z: 415.2(M−23+2H)⁺.

Tert-butyl((1′R,2r,3R,5′S)-8′-(5-bromopyrazin-2-yl)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-yl)carbamate,Intermediate ET

Step a:

To a solution of 2,5-dibromopyrazine (1.00 g, 4.20 mmol) and(1′R,2r,3R,5′S)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-amine(1.53 g, 5.04 mmol, Intermediate EG, 2HCl) in DMSO (10.0 mL) was addeddiisopropylamine (3.40 g, 33.6 mmol, 4.75 mL) at 25° C. Then the mixturewas heated to 100-110° C. and the mixture was stirred at 100-110° C. for3 h. The mixture was cooled to 25° C. and (Boc)₂O (1.65 g, 7.57 mmol,1.74 mL) was added to the mixture and the mixture was stirred at 25° C.for 6 h. The mixture was diluted with H₂O (40.0 mL) and extracted withethyl acetate (40.0 mL×3). The combined organic layers were washed withbrine (30.0 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=20:1 to 16:1,R_(f)=0.50) to afford tert-butyl((1′R,2r,3R,5′S)-8′-(5-bromopyrazin-2-yl)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-yl)carbamate(1.60 g, 3.14 mmol, 75% yield) as a light yellow solid. LC-MS (ESI⁺)m/z: 487.2 (M+H)⁺.

Sodium5-((1′R,2r,3R,5′S)-3-((tert-butoxycarbonyl)amino)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-8′-yl)pyrazine-2-thiolate,Intermediate EU

Step a:

A mixture of tert-butyl((1′R,2r,3R,5′S)-8′-(5-bromopyrazin-2-yl)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-yl)carbamate(1.50 g, 2.92 mmol, Intermediate ET), ethyl 3-mercaptopropanoate (392mg, 2.92 mmol), Pd₂(dba)₃ (134 mg, 146 umol), XantPhos (169 mg, 292umol) and DIPEA (756 mg, 5.85 mmol, 1.02 mL) in dioxane (15.0 mL) wasdegassed and purged with N₂ three times, and the mixture was stirred at80° C. for 2 h under N₂ atmosphere. The mixture was then filteredthrough diatomite, and the reaction mixture was concentrated underreduced pressure to remove dioxane. The residue was purified byprep-HPLC (NH₃.H₂O condition) to afford ethyl3-((5-((1′R,2r,3R,5′S)-3-((tert-butoxycarbonyl)amino)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-8′-yl)pyrazin-2-yl)thio)propanoate(1.40 g, 2.59 mmol, 78% yield) as a white solid. LC-MS (ESI⁺) m/z: 541.6(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.06 (s, 1H), 7.98 (s, 1H), 7.23-7.20(m, 2H), 6.91-6.87 (m, 1H), 6.80-6.78 (m, 1H), 4.84 (d, J=9.2 Hz, 1H),4.64-4.54 (m, 3H), 4.19-4.12 (m, 2H), 3.29-3.25 (m, 2H), 2.72-2.68 (m,2H), 2.43-2.42 (m, 2H), 2.21-2.20 (m, 2H), 2.18-2.17 (m, 2H), 2.07-2.06(m, 1H), 2.06-2.05 (m, 1H), 1.49-1.45 (m, 3H), 1.34 (s, 6H), 1.27 (s,3H).

Step b:

To a solution of ethyl3-((5-((1′R,2r,3R,5′S)-3-((tert-butoxycarbonyl)amino)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-8′-yl)pyrazin-2-yl)thio)propanoate(500 mg, 924 umol) in THE (1.00 mL) was added the solution of EtONa (100mg, 1.48 mmol) in EtOH (1.00 mL) at 0° C. The mixture was stirred at 0°C. for 0.5 h. Then the mixture was warmed to 25° C. and stirred at 25°C. for 1 h. Next, an additional solution of EtONa (31.4 mg, 462 umol) inEtOH (1.00 mL) was added to the mixture at 25° C. and the mixture wasstirred at 25° C. for 1 h. The reaction mixture was concentrated undervacuum at 25° C. to afford sodium5-((1′R,2r,3R,5′S)-3-((tert-butoxycarbonyl)amino)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-8′-yl)pyrazine-2-thiolate(400 mg, 98% crude yield) as a yellow solid. LC-MS (ESI⁺) m/z: 441.2(M-Na+2H)⁺.

5-(5-chloro-6-methyl-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylisoquinolin-1(2H)-one,Intermediate EV

Step a:

To a solution of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (478 mg,1.88 mmol), 5-bromo-2-methylisoquinolin-1(2H)-one (320 mg, 1.34 mmol,CAS #1367905-79-0) in dioxane (6.00 mL) was added KOAc (396 mg, 4.03mmol) and Pd(dppf)Cl₂ (49.2 mg, 67.2 umol) at 25° C. The solution wasdegassed under vacuum and purged with N₂ several times. Then the mixturewas heated to 100° C. and stirred at 100° C. for 4 h. The mixture wascooled to 2 5° C. and concentrated under reduced pressure to give aresidue. The residue was diluted with water (10.0 mL) and ethyl acetate(10.0 mL), then extracted with ethyl acetate (10.0 mL×2). The combinedorganic layer was washed with brine (10.0 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=4/1 to 3/1,R_(f)=0.40) to afford2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one(302 mg, 900 umol, 67% yield) as a white solid. LC-MS (ESI⁺) m/z: 286.1(M+H)⁺.

Step b:

To a solution of2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one(350 mg, 1.04 mmol), 5-chloro-6-methyl-1H-pyrazolo[3,4-b]pyrazine (172mg, 1.02 mmol, Intermediate EY) in DMF (5.00 mL) was added Cu(OAc)₂ (189mg 1.04 mmol) and pyridine (324 mg, 4.09 mmol, 330 uL) at 25° C. Thenthe mixture was heated to 100-110° C. and stirred for 6 h. The mixturewas cooled to 25° C. and poured in H₂O (5.00 mL). The mixture was thenextracted with ethyl acetate (10.0 mL×3). The combined organic layerswere washed with brine (5 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25 * 10 um;mobile phase: [water (0.2% FA)-ACN]; B %: 33%-63%, 11 min) to afford5-(5-chloro-6-methyl-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylisoquinolin-1(2H)-one(20.0 mg, 61.4 umol, 6% yield) as a yellow solid. LC-MS (ESI⁺) m/z:326.1 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.64 (d, J=8.0 Hz, 1H), 8.43 (s,1H), 7.84-7.82 (m, 1H), 7.66 (t, J=7.4 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H),6.27 (d, J=7.6 Hz, 1H), 3.63 (s, 3H), 2.76 (s, 3H).

(R)-2-methyl-N—((R)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)propane-2-sulfinamide,Intermediate EW

Step a:

A solution of tert-butyl(3R)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-carboxylate(500 mg, 1.22 mmol, synthesized via Step a-b of Intermediate CB) in TFA(2 mL) and DCM (10 mL) was stirred at 30° C. for 2 hours. The reactionmixture was then concentrated under reduced pressure. The residue wasdiluted with DCM (10 mL) and MeOH (1 mL) and adjusted to pH=8 with solidK₂CO₃. The solution was filtered and the filtrate was concentrated underreduced pressure to give(R)-2-methyl-N—((R)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)propane-2-sulfinamide(370 mg, 1.19 mmol) as a light yellow solid. LC-MS (ESI⁺) m/z: 309.1(M+H)⁺.

(1′S)-1′,3′-dihydro-8-azaspiro[bicyclo[3.2.1]octane-3,2′-inden]-1′-amine,Intermediate EX (RTX-1136712)

Step a:

Potassium t-butoxide (373 g, 3.33 mol,) was suspended at 0° C. in DME(900 mL) under N₂ atmosphere. Then tosylmethyl isocyanide (390 g, 2.00mol) dissolved in DME (900 mL) was added dropwise keeping thetemperature below 5° C. over 30 min, and was then stirred for additional1 h at 0° C. Next, isopropanol (160 g, 2.66 mol, 204 mL) was addeddropwise at 0° C. and the reaction mixture was stirred for additional 30min. Then tert-butyl(1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (300 g, 1.33 mol)dissolved in DME (900 mL) was added dropwise maintaining the reactiontemperature below 5° C. over 30 min. After the addition, the reactionmixture was stirred 1 hr at 0° C., then warmed to 20° C. and stirred for12 hrs. The reaction mixture was then filtered over celite and theresidue was washed with ethyl acetate (300 mL×2). The organic layerswere combined and evaporated to give the crude product. The crudeproduct was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=50:1 to 30:1) to give tert-butyl(1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate (210 g, 888mmol, 67% yield) as a white solid. ¹HNMR (400 MHz, CDCl₃): δ 4.22 (m,2H), 2.99-2.90 (m, 1H), 2.00 (t, J=2.6 Hz, 4H), 1.85-1.81 (m, 2H), 1.59(d, J=8 Hz, 4H), 1.45 (s, 9H).

Step b:

To a solution of tert-butyl(1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate (100 g, 423mmol) in THE (700 mL) was added LDA (2.00 M, 253 mL) at −70° C. and themixture was stirred at −70° C. for 1 hr. Then to the mixture was added1-bromo-2-(bromomethyl)benzene (111 g, 444 mmol) in THE (300 mL) and themixture was stirred at −70° C. for 2 hrs. The reaction mixture was thenpoured into ice saturated NH₄Cl solution (1.00 L) and extracted withethyl acetate (1.00 L×2). The organic layer was washed with brine (1.00L×1), dried over Na₂SO₄, filtered and concentrated under vacuum to givea residue. The residue was triturated with petroleum ether/acetate ethyl(20/1, 500 mL) to afford tert-butyl(1R,3s,5S)-3-(2-bromobenzyl)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate(145 g, 353 mmol, 84% yield) as a white solid. Stereochemistry wasassigned arbitrarily. LC-MS (ESI⁺) m/z: 351.1 (M−55)⁺; ¹HNMR (400 MHz,CDCl₃): δ 7.59 (d, J=0.8 Hz, 1H), 7.57-7.51 (m, 1H), 7.30-7.28 (m, 1H),7.14-7.16 (m, 1H), 4.30 (s, 1H), 4.19 (s, 1H), 3.08 (s, 2H), 2.23 (t,J=4.8 Hz, 2H), 2.05-1.93 (m, 6H), 1.44 (s, 9H).

Step c:

To a solution of tert-butyl(1R,3s,5S)-3-(2-bromobenzyl)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate(145 g, 353 mmol) in DMA (1.00 L) and H₂O (100 mL) was added TEA (214 g,2.12 mol, 295 mL) and PdCl₂(Amphos)₂ (5.01 g, 7.08 mmol, 5.01 mL) at 20°C. under nitrogen atmosphere. Then the mixture was heated to 100° C. andstirred at 100° C. for 18 hrs. The reaction mixture was then furtherheated to 130° C. and stirred at 130° C. for 24 hrs. The reactionmixture was then poured into saturated NH₄Cl solution (1.00 L) andextracted with ethyl acetate (1.00 L×2). The combined organic layerswere washed with 0.50 N HCl (1.00 L), saturated NaHCO₃ solution (1.00 L)and brine (800 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was triturated with petroleum ether/ethyl acetate (200/1, 500mL) and filtered to give tert-butyl(1R,3s,5S)-1′-oxo-1′,3′-dihydro-8-azaspiro[bicyclo[3.2.1]octane-3,2′-indene]-8-carboxylate(108 g, 321 mmol, 91% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 272.1(M−55)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.71 (d, J=7.6 Hz, 1H), 7.58-7.52 (m,1H), 7.35 (t, J=6.8 Hz, 2H), 4.37 (s, 1H), 4.28 (s, 1H), 3.13-2.99 (m,2H), 2.09-1.92 (m, 6H), 1.82-1.55 (m, 2H), 1.51 (s, 9H).

Step d:

To a solution of tert-butyl(1R,3s,5S)-1′-oxo-1′,3′-dihydro-8-azaspiro[bicyclo[3.2.1]octane-3,2′-indene]-8-carboxylate(100 g, 297 mmol) in Ti(OEt)₄ (330 g, 1.45 mol, 300 mL) was added(R)-2-methylpropane-2-sulfinamide (108 g, 893 mmol) at 25° C. Thereaction mixture was then heated to 90° C. and stirred for 5 days. Thenthe reaction mixture was cooled to −5˜0° C. and 2-Me-THF (200 mL) wasadded, followed by LiBH4 (7.13 g, 327 mmol) carefully portionwise keepthe temperature at −5-0° C. over 2 hrs, The mixture was stirred at −5-0°C. for an additional 2 hrs. The solution was quenched by addition methylalcohol (4.00 mL) at 0-10° C. and2-[2-[bis(2-hydroxyethyl)amino]ethyl-(2-hydroxyethyl)amino]ethanol (500g) was added, and the mixture was stirred for 1 hr at 20° C. To themixture was then added to 1.00 N HCl to adjust the pH=1.00, and themixture was extracted with ethyl acetate (3.00 L×3). The combinedorganic layers were washed with brine (2.00 L×1), dried over anhydrousNa₂SO₄, then filtered through SiO₂ with petroleum ether:ethylacetate=1:1 (3.00 L×3) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=8/1 to 3/1, petroleum ether/ethyl acetate=3/1,R_(f)=0.20) to give tert-butyl(1R,1′S,3s,5S)-1′-(((R)-tert-butylsulfinyl)amino)-1′,3′-dihydro-8-azaspiro[bicyclo[3.2.1]octane-3,2′-indene]-8-carboxylate(52.5 g, 120 mmol, 41% yield) as a brown gum. LC-MS (ESI⁺) m/z: 433.2(M+H)⁺; ¹HNMR (400 MHz, DMSO): δ 7.30-7.28 (m, 1H), 7.18-7.14 (m, 3H),5.50 (d, J=4 Hz, 1H), 4.50 (d, J=5.2 Hz, 1H), 4.06-4.00 (m, 2H), 3.09(d, J=15.2 Hz, 1H), 2.29-2.19 (m, 2H), 2.15-2.06 (m, 1H), 1.83 (s, 3H),1.69 (s, 2H), 1.42 (s, 9H), 1.10 (s, 9H).

Step e:

To a solution of tert-butyl(1R,1′S,3s,5S)-1′-(((R)-tert-butylsulfinyl)amino)-1′,3′-dihydro-8-azaspiro[bicyclo[3.2.1]octane-3,2′-indene]-8-carboxylate(10.0 g, 22.9 mmol) in MeOH (25.0 mL) was added HCl/MeOH (4.00 M, 49.7mL) and the mixture was stirred at 20° C. for 2 hrs. The reactionmixture was then concentrated under reduced pressure to remove MeOH togive a residue. The residue was triturated withdichloromethane/methanol=1/1 (50.0 mL) at 20° C. for 30 min. Then themixture was filtered and the filtrate cake was concentrated underreduced pressure to give(1R,1′S,3s,5S)-1′,3′-dihydro-8-azaspiro[bicyclo[3.2.1]octane-3,2′-inden]-1′-amine(6.50 g, 21.5 mmol, 94% yield, 2HCl) as a white solid. ¹HNMR (400 MHz,DMSO): δ 9.61 (s, 1H), 9.44 (s, 1H), 8.64 (s, 3H), 7.60 (d, J=7.6 Hz,1H), 7.33-7.24 (m, 3H), 4.57 (s, 1H), 3.94 (s, 1H), 3.83 (s, 1H), 3.45(d, J=15.6 Hz, 1H), 2.59 (d, J=15.6 Hz, 1H), 2.34-2.23 (m, 1H),2.11-2.03 (m, 2H), 2.04-1.98 (m, 4H), 1.47 (d, J=10.8 Hz, 1H).

5-Chloro-6-methyl-1H-pyrazolo[3,4-b]pyrazine, Intermediate EY

Step a:

To a stirred solution of 1-(4-methoxybenzyl)-1H-pyrazole-4,5-diamine(159 g, 485 mmol) in EtOH (1.60 L) was added the solution of2-oxopropanoic acid (42.7 g, 485 mmol, 34.2 mL) in EtOH (600 mL)dropwise at 75° C., and the reaction mixture was stirred at 75° C. for 1h. The reaction mixture was then concentrated to give a residue. Theresidue was purified by column chromatography (petroleum ether/ethylacetate=5/1-0/1, R_(f)=0.20) to afford crude product (45.0 g) as ayellow solid. The crude product was further purified by reversed-phaseHPLC (0.1% FA condition) to afford1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyrazin-5-ol (12.0 g,40.9 mmol, 8% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 271.2 (M+H)⁺;¹HNMR (400 MHz, DMSO): δ 12.14 (s, 1H), 7.46 (s, 1H), 7.18 (d, J=8.8 Hz,2H), 6.86 (d, J=8.8 Hz 2H), 5.42 (s, 2H), 3.71 (s, 3H), 2.39 (s, 3H).

Step b:

To a solution of1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyrazin-5-ol (12.0 g,44.4 mmol) in 1,4-dioxane (220 mL) was added POCl₃ (37.7 g, 246 mmol,22.9 mL) dropwise at 0° C. The mixture was then stirred at 80° C. for 12h. The reaction mixture was then concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether/ethyl acetate=20/0-5/1, R_(f)=0.50) to afford5-chloro-1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyrazine (6.00g, 20.7 mmol, 47% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 289.2(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 8.12 (s, 1H), 7.32 (d, J=8.4 Hz, 2H),6.85 (d, J=6.8 Hz, 2H), 5.59 (s, 2H), 3.78 (s, 3H), 2.81 (s, 3H).

Step c:

A solution of5-chloro-1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyrazine inCF₃COOH (47.4 g, 416 mmol, 30.8 mL) was stirred at 70° C. for 5 h. Thereaction mixture was then concentrated in vacuo and the residue wasdissolved in water (200 mL). The pH was adjusted to 8 with saturatedNaHCO₃ (200 mL) and the mixture was extracted with ethyl acetate (500mL×3). The combined organic layers were washed with brine (200 mL×2),dried over Na₂SO₄, filtered and concentrated to afford crude product asa yellow solid. The crude product was purified by reversed-phase HPLC(0.1% HCl condition) to afford5-chloro-6-methyl-1H-pyrazolo[3,4-b]pyrazine (1.40 g, 8.24 mmol, 40%yield) as a light yellow solid. LC-MS (ESI⁺) m/z: 169.2 (M+H)⁺; ¹HNMR(400 MHz, DMSO): δ 14.10 (s, 1H), 8.34 (s, 1H), 2.69 (s, 1H).

4-(5-mercaptopyrazin-2-yl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one,Intermediate EZ

Step a:

A mixture of 2-bromo-5-methoxypyrazine (5.08 g, 26.9 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carbonitrile(6.00 g, 25.7 mmol, CAS #1310384-20-3), K₂CO₃ (10.6 g, 77.1 mmol) andPd(dppf)Cl₂ (1.88 g, 2.57 mmol, CAS #72287-26-4) in dioxane (150.00 mL)and H₂O (15.00 mL) was stirred at 100° C. for 12 hours under N₂atmosphere. The reaction mixture was then concentrated and H₂O (200 mL)was added. The mixture was extracted with ethyl acetate (300 mL×3) andthe combined organic layers were washed with brine (500 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether:ethyl acetate=100:0 to 100:30) to afford4-(5-methoxypyrazin-2-yl)cyclohex-3-ene-1-carbonitrile (4.80 g, 87%yield) as a white solid. LC-MS (ESI⁺) m/z: 216.0 (M+H)⁺.

Step b:

4-(5-Methoxypyrazin-2-yl)cyclohex-3-ene-1-carbonitrile (1.90 g, 8.82mmol) and 1-bromo-2-(bromomethyl)benzene (2.42 g, 9.70 mmol, CAS#3433-80-5) were dissolved in THF (200 mL). Then, LDA (4.85 mL, 9.70mmol, 2M in THF) was added dropwise into the mixture at −10° C. Themixture was stirred at 0° C. for 0.5 hour, then the mixture was thenwarmed to 25° C. for 1 hour. Another batch of LDA (4.41 mL, 8.82 mmol, 2M in THF) was added dropwise into the mixture at −10° C. The mixture wasstirred at 0° C. for 0.5 hour, then the mixture was then warmed to 25°C. for 1 hour. The combined reaction mixture was quenched by addition ofsat. NH₄Cl (200 mL). The mixture was extracted with ethyl acetate (200mL×3) and the combined organic layers were washed with brine (200 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:0 to 100:20) to afford1-[(2-bromophenyl)methyl]-4-(5-methoxypyrazin-2-yl)cyclohex-3-ene-1-carbonitrile(3.00 g, 89% yield) as a yellow solid. LC-MS (ESI+) m/z: 383.7, 385.7(M+H)⁺.

Step c:

1-[(2-Bromophenyl)methyl]-4-(5-methoxypyrazin-2-yl)cyclohex-3-ene-1-carbonitrile(3.00 g, 7.80 mmol), PdCl₂(AmPhos)₂ (276 mg, 390 μmol, CAS #887919-35-9)and TEA (4.31 mL, 31.2 mmol) were placed into DMA (50.00 mL) and H₂O(1.00 mL). The reaction mixture was evacuated and refilled three timesusing N₂. The reaction mixture was stirred at 120° C. for 12 hours. Thenthe mixture was concentrated to give a residue. The residue was purifiedby flash silica gel chromatography (petroleum ether:ethyl acetate=100:0to 100:20) to afford4-(5-methoxypyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one(2.20 g, 92% yield) as a yellow oil. LC-MS (ESI+) m/z: 307.0 (M+H)⁺.

Step d:

4-(5-Methoxypyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one(1.60 g, 5.22 mmol) was dissolved in MeOH (90.0 mL) and THE (10.0 mL),then 10% Pd/C (160.0 mg, wet) was added. The reaction mixture wasevacuated and refilled three times using H₂. The reaction mixture wasthen stirred at 25° C. for 12 hours under H₂ (15 psi). The mixture wasthen filtered and the filtrate was concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether:ethyl acetate=100:20) to afford4-(5-methoxypyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(1.20 g, 75% yield) as a colorless oil. LC-MS (ESI+) m/z: 308.9 (M+H)⁺.

Step e:

4-(5-Methoxypyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(900.0 mg, 2.91 mmol) was placed into HBr/AcOH (33%, 15.0 mL), and thereaction mixture was stirred at 100° C. for 1 hour. Then the mixture wasconcentrated to give a residue. The reaction mixture was concentratedand H₂O (10.0 mL) was added, then the solution was extracted with DCM(20.0 mL×3). The combined organic layers were washed with brine (30.0mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(DCM:MeOH=100:0 to 100:5) to afford4-(5-hydroxypyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(80.0 mg, 58% yield) as a yellow solid. LC-MS (ESI+) m/z: 295.1 (M+H)⁺.

Step f:

4-(5-Hydroxypyrazin-2-yl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (500mg, 1.69 mmol) was dissolved in DMF (10 mL). BOP (2.23 g, 5.06 mmol) wasadded and the reaction mixture was stirred at 20° C. for 5 min. Next,2-ethylhexyl 3-sulfanylpropanoate (575 μL, 2.53 mmol) and DBU (1.50 mL,10.1 mmol) were added and the reaction mixture was stirred at 20° C. for1 hour. Additional 2-ethylhexyl 3-sulfanylpropanoate (1.91 mL, 8.45mmol) was added and the mixture was stirred at 20° C. for 12 hours. Themixture was then diluted with EtOAc (30 mL) and H₂O (20 mL), and thepartitioned layers were separated. The aqueous phase was extracted withethyl acetate (20 mL×2) and the combined organic layers were washed withbrine (30 mL×3), dried over anhydrous Na₂SO₄, filtered and concentratedto give a residue. The residue was purified by flash silica gelchromatography (petroleum ether/ethyl acetate=100:0 to 100:15) to afford2-ethylhexyl3-((5-(1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-yl)pyrazin-2-yl)thio)propanoate(410 mg, 49% yield) as a colorless oil. LC-MS (ESI⁺) m/z: 495.2 (M+H)⁺.

Step g:

2-Ethylhexyl3-((5-(1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-yl)pyrazin-2-yl)thio)propanoate(220.0 mg, 444 μmol) was dissolved in THE (1.00 mL). The reactionmixture was cooled to −78° C. and t-BuOK (1.33 mL, 1.33 mmol, 1 M inTHF) was added dropwise over 10 min under N₂. The reaction mixture wasthen stirred at −78° C. for 20 min. The reaction mixture was thendiluted with DCM (30 mL) and acidified with HCl/MeOH (2 N) to pH=6 at−78° C. The mixture was washed with H₂O (20 mL) and brine (20 ml). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedto give4-(5-mercaptopyrazin-2-yl)spiro[cyclohexane-1,2′-inden]-1′(3′)-one(137.0 mg, 441 μmol, 100% crude yield) as a yellow solid. LC-MS (ESI+)m/z: 311.0 (M+H)⁺.

Tert-butylN-[(3S)-1′-(1-methyl-6-oxo-5-sulfanyl-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate FA

Step a:

A mixture of tert-butylN-[(3S)-1′-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(400.0 mg, 745 μmol, Intermediate DQ), Pd₂(dba)₃ (68.2 mg, 74 μmol),XantPhos (86.2 mg, 149 μmol), 2-ethylhexyl butyrate (162.0 mg, 745 μmol)and DIPEA (367 μL, 2.2 mmol) in dioxane (10.00 mL) was stirred at 100°C. for 12 hours under N₂ atmosphere. The mixture was concentrated andwas purified by silica gel chromatography (ethyl acetate in petroleumether=0% to 60%) to afford 2-ethylhexyl3-({2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}sulfanyl)propanoate(236.0 mg, 51% yield) as a yellow oil. LC-MS (ESI+) m/z: 627.3 (M+H)⁺.

Step b:

To a mixture of 2-ethylhexyl3-({2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}sulfanyl)propanoate(236.0 mg, 376 μmol) in anhydrous THF (1.50 mL) was added t-BuOK (1.12mL, 1.1 mmol, 1M in THF) over 10 min at −78° C. The mixture was stirredat −78° C. for 0.5 hour under N₂ atmosphere. The reaction mixture wasthen diluted with DCM (30 mL) and acidified with HCl/EtOAc (2 N, 1.00mL) to pH=6 at −78° C. The mixture was washed with brine (20 mL), andthe organic layer were dried over anhydrous Na₂SO₄, filtered andconcentrated to give tert-butylN-[(3S)-1′-(1-methyl-6-oxo-5-sulfanyl-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 72% crude yield) as a red oil. LC-MS (ESI⁺) m/z: 443.1(M+H)⁺.

Methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-sulfanylpyrazine-2-carboxylate,Intermediate FB

Step a:

Methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(500 mg, 966 μmol, Intermediate DN), 2-ethylhexyl 3-sulfanylpropanoate(231 mg, 1.06 mmol), Pd₂(dba)₃ (88.4 mg, 96.6 umol), Xantphos (111 mg,193 umol), and DIPEA (249 mg, 1.93 mmol) were placed into dioxane (20mL). The reaction mixture was evacuated and refilled 3 times using N₂and then stirred at 100° C. for 10 hours. The reaction mixture was thenconcentrated, H₂O (20 mL) was added, and the solution was extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated togive a residue. The residue was purified by flash silica gelchromatography (petroleum ether:ethyl acetate=100:40) to afford methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)pyrazine-2-carboxylate(450 mg, 71% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 655.3 (M+H)⁺.

Step b:

The compound of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)pyrazine-2-carboxylate(250.0 mg, 381.0 μmol) was dissolved in THE (1.5 mL). The reactionmixture was cooled to −78° C. and t-BuOK (1.14 mL, 1.1 mmol, 1 M in THF)was added dropwise over 10 min under N₂. The reaction mixture wasstirred at −78° C. for 0.5 hour. The reaction mixture was diluted withDCM (20 mL) and acidified with HCl/MeOH (4 N) to pH=5-6 at −78° C. Themixture was washed with H₂O (20 mL) and brine (20 ml). The organic layerwere dried over anhydrous Na₂SO₄, filtered and concentrated to give3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-sulfanylpyrazine-2-carboxylate(179.0 mg, 100% crude yield).

tert-butylN-[(3S)-1′-(1-benzyl-5-iodo-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate FC

Step a:

2-Chloro-5-iodo-3,4-dihydropyrimidin-4-one (1.5 g, 5.8 mmol, synthesizedvia Step a of Intermediate DP), K₂CO₃ (2.4 g, 17.5 mmol) and benzylbromide (2.0 g, 11.6 mmol) were added in DMF (40 mL). The reactionmixture was stirred at 50° C. for 2 hours. The mixture was diluted withEtOAc (100 mL), washed with H₂O (40 mL×2), brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether:ethyl acetate=100:0 to 100:20) to afford3-benzyl-2-chloro-5-iodo-3,4-dihydropyrimidin-4-one (750.0 mg, 2.2 mmol,37% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 346.8 (M+H)⁺.

Step b:

3-Benzyl-2-chloro-5-iodo-3,4-dihydropyrimidin-4-one (750.0 mg, 2.2mmol), tert-butylN-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate (783.0mg, 2.6 mmol, Intermediate EF) and TEA (1.5 mL, 10.8 mmol) were placedinto DMF (15 mL). The reaction mixture was evacuated and refilled threetimes using N₂, then the reaction mixture was stirred at 70° C. for 2hours. The reaction mixture was then diluted with water (40 mL), andextracted with EtOAc (80 mL×2). The organic layers were washed with H₂O(40 mL) and brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (20 g column, EtOAc in petroleum ether from 0%-30%) togive tert-butylN-[(3S)-1′-(1-benzyl-5-iodo-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(730.0 mg, 1.2 mmol, 55% yield) as a white solid. LC-MS (ESI⁺) m/z:613.1 (M+H)⁺.

(R)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine, IntermediateFD

Step a:

BF₃.Et₂O (78.0 g, 263 mmol, 67.8 mL, 48% solution) was added dropwise toa solution of propane-1,3-dithiol (119 g, 1.11 mol, 111 mL) and2,5-difluorobenzaldehyde (150 g, 1.06 mol, 114 mL) in DCM (750 mL) at 0°C. The reaction was then stirred at 25° C. for 1 hr. The reactionmixture was then diluted with water (500 mL) and extracted with CH₂C2(500 mL×3) and the organic layer was concentrated under vacuum. Theresidue was slurried in petroleum ether (400 mL) and collected withfiltration to give 2-(2,5-difluorophenyl)-1,3-dithiane (180 g, 774 mmol,73% yield) as a white solid. ¹HNMR (400 MHz, CDCl₃): δ 7.36 (dd,J_(ab)=2.8 Hz, J_(ac)=8.4 Hz, H), 7.02-6.97 (m, 2H), 5.50 (s, 1H),3.15-3.08 (m, 2H), 2.95-2.91 (m, 2H), 2.21-2.17 (m, H), 1.97-1.93 (m,H).

Step b:

A solution of 2-(2,5-difluorophenyl)-1,3-dithiane (100 g, 430 mmol) inTHE (400 mL) was cooled to −50˜−40° C. To the mixture was then added LDA(2 M, 258 mL) at −50˜−40° C. and the mixture was warmed to −30˜−20° C.for 1 hr. Then the mixture was cooled to −50˜−40° C. and to the mixturewas added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (90.0g, 451 mmol) in THE (200 mL) dropwise. After the addition, the mixturewas stirred at −50˜−40° C. for another 1 hr. The mixture was thenquenched with sat.NH₄Cl (600 mL) and extracted with ethyl acetate (400mL×2) at 25° C. The organic phase was dried with Na₂SO₄, filtered andthe filtrate was concentrated in vacuo to give the crude product. Thecrude product was triturated with petroleum ether (400 mL) at 25° C. for1 hr, and then filtered. The residue was dried in vacuo to givetert-butyl4-(2-(2,5-difluorophenyl)-1,3-dithian-2-yl)-4-hydroxypiperidine-1-carboxylate(132 g, 286 mmol, 67% yield) as white solid. LC-MS (ESI⁺) m/z: 332.1(M−100)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.85-7.80 (m, H), 7.05-7.00 (m, 2H),3.91 (s, 2H), 2.97 (s, 2H), 2.86-2.81 (m, 2H), 2.66-2.61 (m, 2H), 2.55(s, H), 1.90-1.87 (m, 2H), 1.79 (t, J=16.4 Hz, 3H), 1.41 (s, 9H).

Step c:

To a solution of tert-butyl4-(2-(2,5-difluorophenyl)-1,3-dithian-2-yl)-4-hydroxypiperidine-1-carboxylate(147 g, 318 mmol), pyridine (50.4 g, 637 mmol, 51.4 mL), TBAB (20.56 g,63.77 mmol) in H₂O (73.5 mL) and CH₂Cl₂ (735 mL) was added pyridine-HBr₃(203 g, 637 mmol) at 0° C. The mixture was then stirred at 25° C. for 2hrs. The solution was then poured into water (750 mL) and extracted withCH₂Cl₂ (500 mL×3). The combined organic layers were washed with brine(500 mL), dried over Na₂SO₄, then filtered. The filtrate wasconcentrated under vacuum to give tert-butyl4-(2,5-difluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (109 g, quant.crude yield) as a yellow solid.

Step d:

To a mixture of tert-butyl4-(2,5-difluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (109 g, 319mmol) in dioxane (440 mL) was added t-BuOK (53.7 g, 478 mmol) at 25° C.The mixture was then stirred at 70° C. for 2 hrs. The solution was thenpoured into water (1.00 L) and extracted with ethyl acetate (500 mL×3).The combined organic layers were washed with brine (500 mL), dried overNa₂SO₄, then filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=1:0 to 8:1, R_(f)=0.30, petroleum ether:ethylacetate=3:1). The mixture was further triturated with petroleum ether(50.0 mL) to give tert-butyl5-fluoro-3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (32.0g, 93.1 mmol, 29% yield) as a light yellow solid. LC-MS (ESI⁺) m/z:265.8 (M−55)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.38-7.32 (m, H), 7.32-7.27 (m,H), 7.12 (dd, J_(ab)=4.0 Hz, J_(ac)=9.2 Hz, H), 4.15 (s, 2H), 3.22 (s,2H), 1.98-1.90 (m, 2H), 1.61 (d, J=13.6 Hz, 2H), 1.50 (s, 9H).

Step e:

To a solution of tert-butyl5-fluoro-3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (31.0g, 90.2 mmol) in 2-methyl tetrahydrofuran (217 mL) was added Ti(OEt)₄(61.8 g, 271 mmol, 56.1 mL) and (R)-2-methylpropane-2-sulfinamide (21.9g, 180 mmol) at 25° C. The mixture was then stirred at 90° C. for 18hrs. Then the reaction mixture was cooled to 0° C., and LiBH₄ (2.94 g,134.9 mmol) was added at 0-10° C., and the mixture was stirred at 0-10°C. for 2 hrs. The mixture was quenched by addition methyl alcohol (15.0mL) at 0-10° C. and2-[2-[bis(2-hydroxyethyl)amino]ethyl-(2-hydroxyethyl)amino]ethanol (50.0g) was added, and the mixture was stirred for 30 min at 25° C. To themixture was added to 10% citric acid solution (800 mL) and the solutionwas extracted with ethyl acetate (400 mL×3). The combined organic layerwas washed with brine (80.0 mL), dried over anhydrous Na₂SO₄, thenfiltered through SiO₂ and evaporated under reduced pressure to give ayellow oil. The yellow oil was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=10:1 to 2:1, R_(f)=0.30, 0.35) to give ayellow solid. The yellow solid was slurred in methyl tertiary butylether (120 mL) and filtered to give a white solid. The white solid waspurified by column chromatography (SiO₂, petroleum ether:ethylacetate=10:1 to 2:1, R_(f)=0.30) to give tert-butyl(R)-3-(((R)-tert-butylsulfinyl)amino)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate(15.0 g, 34.4 mmol, 38% yield) as a white solid. ¹HNMR (400 MHz, DMSO):δ 7.06-7.01 (m, H), 6.82 (dd, J=4.00 Hz, J=8.40 Hz, H), 6.13 (d, J=10.80Hz, H), 4.65 (d, J=10.40 Hz, H), 4.01-3.88 (m, H), 3.04 (s, H),1.85-1.69 (m, 4H), 1.42 (s, 9H), 1.19 (s, 9H).

Step f:

A mixture of tert-butyl(R)-3-(((R)-tert-butylsulfinyl)amino)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate(16.0 g, 37.5 mmol) in methyl alcohol (32.0 mL) were added HCl/MeOH(4.00 M, 80.0 mL) at 25° C. and the mixture was stirred at 25° C. for 2hrs. The reaction mixture was then concentrated in vacuo to give a whitesolid. The white solid was slurred in ethyl acetate (50.0 mL), filtered,and the cake was dried in vacuo to give(R)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (10.0 g, 33.3mmol, 89% yield, 2HCl) as a white solid. ¹HNMR (400 MHz, DMSO): δ 9.71(d, J=8.00 Hz, H), 9.39 (d, J=9.20 Hz, H), 9.18 (s, H), 9.39 (dd, J=2.40Hz, J=8.00 Hz, H), 7.20-7.15 (m, H), 9.39 (d, J=9.20 Hz, H), 9.39 (dd,J=4.00 Hz, J=8.80 Hz, H), 4.75 (s, H), 4.75 (s, H), 3.42 (d, J=12.80 Hz,H), 3.21 (d, J=12.00 Hz, H), 3.03 (s, 2H), 2.43-2.37 (m, H), 2.17 (d,J=13.20 Hz, H), 1.99 (d, J=12.40 Hz, H), 1.87 (d, J=12.40 Hz, H).

Tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate,Intermediate FE

Step a:

A mixture of 2,5-dibromopyrazine (200.0 mg, 0.8 mmol, CAS #23229-25-6),(3R)-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminedihydrochloride (272.0 mg, 0.9 mmol, Intermediate FD) and TEA (580 μL,4.2 mmol) in DMF (10 mL) was stirred at 80° C. for 2.5 hours. The crudesolution was used directly in the next step. LC-MS (ESI⁺) m/z: 361.6(M−NH₂)⁺.

Step b:

To the crude solution of(R)-1′-(5-bromopyrazin-2-yl)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine(318.0 mg, 0.8 mmol) in DMF (10 mL) was added Boc₂O (383 μL, 1.7 mmol)at 15° C. The reaction mixture was stirred at 15° C. for 12 hours. Thereaction mixture was then diluted with water (30 mL), and extracted withEtOAc (50 mL×2). The organic layers were washed with H₂O (40 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (20 g column, EtOAc inpetroleum ether from 0%˜10%) to give tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(270.0 mg, 0.6 mmol, 67% yield in two steps) as a yellow solid. LC-MS(ESI⁺) m/z: 479.0 (M+H)⁺.

Tert-butylN-[(3R)-5-fluoro-1′-(5-sulfanylpyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate,Intermediate FF

Step a:

A mixture of tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(270.0 mg, 0.6 mmol, Intermediate FE), 2-ethylhexyl 3-sulfanylpropanoate(135.0 mg, 0.6 mmol, CAS #50448-95-8), Pd₂(dba)₃ (51.5 mg, 0.06 mmol),XantPhos (65.1 mg, 0.1 mmol) and DIPEA (276 μL, 1.7 mmol) in dioxane (10mL) was stirred at 100° C. for 12 hours under N₂ atmosphere. Thereaction mixture was poured into H₂O (20 mL) and extracted with EtOAc(40 mL×2). The combined organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by silica gelchromatography (ethyl acetate in petroleum ether=0% to 15%) to afford2-ethylhexyl3-({5-[(3R)-3-{[(tert-butoxy)carbonyl]amino}-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)propanoate(220.0 mg, 0.4 mmol, 63% yield) as a yellow solid. LC-MS (ESI⁺) m/z:617.2 (M+H)⁺.

Step b:

To the mixture of 2-ethylhexyl3-({5-[(3R)-3-{[(tert-butoxy)carbonyl]amino}-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)propanoate(220.0 mg, 0.4 mmol) in anhydrous THE (1.5 mL) was added t-BuOK (1.1 mL,1.1 mmol, 1 M in THF) over 10 min at −78° C., and the resulting mixturewas stirred at −78° C. for 0.5 hour under N₂ atmosphere. The reactionmixture was then diluted with DCM (30 mL) and acidified with HCl/EtOAc(2 N, 1 mL) to pH=6 at −78° C. The mixture was washed with H₂O (20 mL)and brine (20 ml). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated to give tert-butylN-[(3R)-5-fluoro-1′-(5-sulfanylpyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(154.0 mg, 100% crude yield) as a red oil.

6-Chloro-1-methyl-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydropyridin-2-one,Intermediate FG

Step a:

A mixture of 3-bromo-6-chloro-2-methoxypyridine (1.0 g, 4.5 mmol, CAS#1211526-62-3), 1,2,3,4-tetrahydroquinoline (656.0 mg, 4.9 mmol, CAS#25448-04-8), Pd₂(dba)₃ (616.0 mg, 0.7 mmol), t-BuONa (646.0 mg, 6.7mmol) and XantPhos (1.6 g, 2.7 mmol) were added into toluene (30 mL).The reaction mixture was evacuated and refilled three times using N₂ andthe reaction mixture was stirred at 100° C. for 12 hours. The reactionmixture was then filtered and washed with EtOAc (80 mL×2). The filtratewas washed with H₂O (30 mL×2) and the organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash silica gel chromatography (40 g column, EtOAc in petroleum etherfrom 0%˜5%) to give1-(6-chloro-2-methoxypyridin-3-yl)-1,2,3,4-tetrahydroquinoline (1.3 g,4.5 mmol, 101% crude yield) as a yellow oil. LC-MS (ESI+) m/z: 274.9(M+H)⁺.

Step b:

A mixture of1-(6-chloro-2-methoxypyridin-3-yl)-1,2,3,4-tetrahydroquinoline (1.3 g,4.5 mmol) and TMSI (6.5 mL, 45.3 mmol) in DCM (20 mL) was stirred at 50°C. for 12 hours. Then additional TMSI (6.5 mL, 45.3 mmol) was added andthe resulting mixture was stirred at 50° C. for 50 hours. The reactionmixture was then diluted with DCM (60 mL) and H₂O (40 mL), and extractedwith DCM (50 mL×2). The organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (20 g column, EtOAc inpetroleum ether from 0%˜10%) to give6-chloro-3-(1,2,3,4-tetrahydroquinolin-1-yl)pyridin-2-ol (550.0 mg, 2.1mmol, 47% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 260.9 (M+H)⁺.

Step c:

To a solution of NaH (166.0 mg, 4.2 mmol, 60% dispersion in mineral oil)in DMF (10 mL) was added6-chloro-3-(1,2,3,4-tetrahydroquinolin-1-yl)pyridin-2-ol (550.0 mg, 2.1mmol) at 0° C. under N₂ atmosphere. The mixture was stirred at 0° C. for20 min, then iodomethane (326 μL, 5.3 mmol) was added and the mixturewas allowed to warm up to 15° C. and stirred at this temperature for 1hour under N₂ atmosphere. The mixture was then quenched with MeOH (1 mL)diluted with H₂O (40 mL), and the aqueous phase was extracted with ethylacetate (100 mL×3). The combined organic layers were washed with water(30 mL×2), followed by brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byflash silica gel chromatography (20 g column, ethyl acetate/petroleumether=0/100 to 30/100) to afford6-chloro-1-methyl-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydropyridin-2-one(400.0 mg, 1.5 mmol, 69% yield) as a yellow oil. LC-MS (ESI+) m/z: 275.0(M+H)⁺.

tert-butyl(S)-(1′-(6-iodo-5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate FH

Step a:

A mixture of 2-bromoimidazo[2,1-b][1,3,4]thiadiazole (3.0 g, 14.7 mmol,CAS #1137142-58-5), (1S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminedihydrochloride (4.04 g, 14.7 mmol, Intermediate I) and DIPEA (12.8 mL,73.5 mmol) in DMF (50.0 mL) was stirred at 100° C. for 3 hours. Thereaction mixture was used directly in the next step. LC-MS (ESI+) m/z:326.2 (M+H)⁺.

Step b:

To a mixture of(1S)-1′-{imidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(4.7 g, 14.4 mmol) in DMF (50.0 mL) was added (Boc)₂O (4.94 mL, 21.6mmol), and the resulting mixture was stirred at 20° C. for 1 hour. Themixture was then diluted with ethyl acetate (150.0 mL), and washed withH₂O (80.0 mL×3). The organic phase was washed with brine (50.0 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 75%) to afford tert-butylN-[(1S)-1′-{imidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(4.10 g, 9.63 mmol, 67% yield over 2 steps) as a white solid. LC-MS(ESI+) m/z: 426.0 (M+H)⁺.

Step c:

To a mixture of tert-butylN-[(1S)-1′-{imidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(2.0 g, 4.69 mmol) in DMF (30.0 mL) at 0° C. was added NIS (1.15 g, 5.15mmol), and the resulting mixture was stirred at 0° C. for 3.5 hours. Themixture was then diluted with ethyl acetate (80.0 mL), and washed withH₂O (50.0 mL×2). The organic phase was washed with brine (30.0 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 45%) to afford tert-butylN-[(1S)-1′-{5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(1.75 g, 3.17 mmol, 68% yield) as a yellow solid. Minor bis-iodinationproduct was also formed during the reaction and removed duringpurification. LC-MS (ESI+) m/z: 551.9 (M+H)⁺.

Step d:

A mixture of tert-butylN-[(1S)-1′-{5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(1.7 g, 3.08 mmol), methylboronic acid (921 mg, 15.4 mmol), Cs₂CO₃ (2.00g, 6.16 mmol) and Pd(PPh₃)₄ (355 mg, 308 μmol) in 1,4-dioxane (20.0 mL)was stirred under microwave irradiation at 135° C. for 1 hour under N₂atmosphere. The mixture was then concentrated in vacuo to give aresidue, which was dissolved in ethyl acetate (30.0 mL), washed with H₂O(20.0 mL×2) and brine (15.0 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue,which was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 95%) to afford tert-butylN-[(1S)-1′-{5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(780 mg, 1.77 mmol, 57% yield) as a yellow solid. LC-MS (ESI+) m/z:440.2 (M+H)⁺.

Step e:

A mixture of tert-butylN-[(1S)-1′-{5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(1.3 g, 1.77 mmol, purity: 60%) and NIS (595 mg, 2.65 mmol) in DMF (15.0mL) was stirred at 15° C. for 1.5 hours. The mixture was then dilutedwith ethyl acetate (50.0 mL), and washed with H₂O (25.0 mL×3). Theorganic phase was washed with brine (20.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 40%) to afford tert-butylN-[(1S)-1′-{6-iodo-5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(460 mg, 813 μmol, 46% yield) as a yellow solid. LC-MS (ESI+) m/z: 566.0(M+H)⁺.

(R)-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine, IntermediateFI

Step a:

BF₃.Et₂O (78.0 g, 263 mmol, 67.8 mL, 48% solution) was added dropwise toa solution of 2,4-difluorobenzaldehyde (150 g, 1.06 mol, 114 mL) andpropane-1,3-dithiol (119 g, 1.11 mol, 111 mL) in CH₂Cl₂ (750 mL) at 0°C. The reaction was then stirred at 25° C. for 1 hr. The reactionmixture was then quenched by water (500 mL) and extracted with CH₂Cl₂(300 mL×2). The organic layer was dried over Na₂SO₄, filtered and thefiltrate was concentrated under vacuum. The residue was slurried inpetroleum ether (50.0 mL) and collected by filtration to give2-(2,4-difluorophenyl)-1,3-dithiane (192 g, 826 mmol, 78% yield) as awhite solid. LC-MS (ESI⁺) m/z: 233.0 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ7.61-7.55 (m, H), 6.88-6.81 (m, H), 6.80-6.77 (m, H), 5.47 (s, 1H),3.12-3.05 (m, 2H), 2.91-2.88 (m, 2H), 2.18-2.13 (m, H), 1.92-1.89 (m,H).

Step b:

A solution of 2-(2,4-difluorophenyl)-1,3-dithiane (123 g, 529 mmol) inTHE (615 mL) was cooled to −50˜−40° C. To the mixture was added LDA (2M, 317 mL) at −50˜−40° C. Then the mixture was warmed to −30˜−20° C. for1 hr. Next, the mixture was cooled to −50˜−40° C. and to the mixture wasadded TMSCl (60.4 g, 555 mmol, 70.5 mL) dropwise. After the addition,the mixture was stirred at −50˜−40° C. for another 1 hr. To the mixturewas added additional LDA (2 M, 397 mL) at −50˜−40° C. Then the mixturewas warmed to −30˜−20° C. for 1 hr. Then the mixture was cooled to−50˜−40° C. and to the mixture was added a solution of tert-butyl4-oxopiperidine-1-carboxylate (110 g, 555 mmol) in THE (246 mL) at−50˜−40° C. The mixture was stirred at −50˜−40° C. for 1 hr. The mixturewas then quenched with aqueous NH₄Cl solution (1.50 L) and extractedwith ethyl acetate (1.00 L×2) at 25° C. The organic phase was dried withNa₂SO₄, filtered and the filtrate was concentrated in vacuo to give acrude product. The mixture was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=1:0 to 10:1, petroleum ether:ethylacetate=3:1, R_(f)=0.45) to give tert-butyl4-(2-(2,4-difluoro-3-(trimethylsilyl)phenyl)-1,3-dithian-2-yl)-4-hydroxypiperidine-1-carboxylate(234 g, 459 mmol, 87% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 504.2(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.98-7.92 (m, H), 6.77 (t, J=8.0 Hz,H), 3.81 (s, 2H), 2.88 (s, 2H), 2.74 (t, J=7.2 Hz, 2H), 2.52-2.45 (m,2H), 1.78-1.75 (m, 2H), 1.64-1.60 (t, J=7.2 Hz, 4H), 1.31 (s, 9H), 0.26(s, 9H).

Step c:

To a solution of tert-butyl4-(2-(2,4-difluoro-3-(trimethylsilyl)phenyl)-1,3-dithian-2-yl)-4-hydroxypiperidine-1-carboxylate(210 g, 412 mmol), pyridine (65.2 g, 824 mmol, 66.5 mL), and TBAB (26.5g, 82.4 mmol) in CH₂Cl₂ (1.05 L) and H₂O (105 mL) was pyridine-HBr₃ (263g, 824 mmol) at 0° C. The mixture was then stirred at 25° C. for 2 hrs.The solution was poured into water (1.50 L) and extracted with CH₂Cl₂(800 mL×3). The combined organic layers were washed with brine (1.50 L),dried over Na₂SO₄, then filtered and the filtrate was concentrated undervacuum to give tert-butyl4-(2,4-difluoro-3-(trimethylsilyl)benzoyl)-4-hydroxypiperidine-1-carboxylate(171 g, quant. crude yield) as a brown oil. LC-MS (ESI⁺) m/z: 313.9(M−100)⁺;

Step d:

To a solution of tert-butyl4-(2,4-difluoro-3-(trimethylsilyl)benzoyl)-4-hydroxypiperidine-1-carboxylate(171 g, 413 mmol) in dioxane (650 mL) was added t-BuOK (69.6 g, 620mmol) at 25° C. The mixture was then stirred at 70° C. for 2 hrs. Thesolution was poured into water (1.00 L) and extracted with ethyl acetate(800 mL×3). The combined organic layers were washed with brine (1.00 L),dried over Na₂SO₄, then filtered and evaporated under reduced pressure.The crude product was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=100:1 to 25:1, R_(f)=0.30, petroleum ether:ethylacetate=3:1) to give tert-butyl6-fluoro-3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (52.0g, 160 mmol, 39% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 222.1(M−100)⁺; ¹HNMR (400 MHz, DMSO): δ 7.78 (dd, J_(ab)=2.0 Hz, J_(ac)=8.4Hz, H), 7.27 (dd, J_(ab)=2.0 Hz, J_(ac)=9.6 Hz, H), 7.07-7.04 (m, H),4.00 (d, J=13.6 Hz, 2H), 3.14 (s, 2H), 2.88 (s, 2H), 2.74 (t, J=7.2 Hz,2H), 1.74-1.64 (m, 4H), 1.43 (s, 9H).

Step e:

To a solution of tert-butyl6-fluoro-3-oxo-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (40.0g, 123 mmol) in 2-Me-THF (80.0 mL) was added Ti(OEt)₄ (84.5 g, 370 mmol,76.9 mL) and (R)-2-methylpropane-2-sulfinamide (29.9 g, 247 mmol) at 15°C. The mixture was then stirred at 90° C. for 18 hrs. Next, to themixture was added LiBH₄ (2.96 g, 135 mmol) at 0° C., and the mixture wasstirred at 15° C. for 2 hrs. The solution was quenched by MeOH (20.0 mL)at 0° C. and2-[2-[bis(2-hydroxyethyl)amino]ethyl-(2-hydroxyethyl)amino]ethanol (40.0g) was added, and the mixture was stirred for 1 hr at 15° C. The mixturewas adjusted to pH=1 with 0.5 N HCl and extracted with ethyl acetate(600 mL×3). The organic layers were washed with brine (800 mL), driedover Na₂SO₄, then filtered through SiO₂ and the filtrate wasconcentrated under vacuum. The mixture was then triturated with MTBE(100 mL) to give tert-butyl(R)-3-(((R)-tert-butylsulfinyl)amino)-6-fluoro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate(27.0 g, 62.1 mmol, 50% yield) as a white solid. LC-MS (ESI⁺) m/z: 371.1(M−55)⁺; ¹HNMR (400 MHz, DMSO): δ 7.26 (t, J=6.4 Hz, H), 6.75 (dd,J_(ab)=2.4 Hz, J_(ac)=9.6 Hz, 2H), 6.09 (d, J=10.4 Hz, H), 4.61 (d,J=10.4 Hz, H), 3.96 (t, J=16.8 Hz, 2H), 3.04 (s, 2H), 1.89-1.82 (m, 4H),1.42 (s, 9H), 1.17 (s, 9H).

Step f:

To a solution of tert-butyl(R)-3-(((R)-tert-butylsulfinyl)amino)-6-fluoro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate(15.0 g, 34.5 mmol) in MeOH (30.0 mL) was added HCl/MeOH (4 M, 75.0 mL)at 15° C. and the mixture was stirred at 15° C. for 1 hr. The mixturewas concentrated under vacuum. The crude product was triturated withpetroleum ether:ethyl acetate=3:1 (40.0 mL) at 15° C. for 1 hr to give(R)-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (10.08 g, 34.1mmol, 99% yield, 2HCl) as a white solid. LC-MS (ESI⁺) m/z: 347.8(M−16)⁺; ¹HNMR (400 MHz, DMSO): δ 9.58 (s, H), 9.36 (s, H), 9.03 (s,3H), 7.79 (dd, J_(ab)=5.6 Hz, J_(ac)=8.0 Hz, H), 6.90-6.83 (m, 2H), 4.72(s, H), 3.43 (s, H), 3.24 (d, J=12.8 Hz, H), 3.06 (s, H), 2.50-2.41 (m,H), 2.19 (d, J=12.4 Hz, H), 2.02-2.00 (m, H), 1.91 (d, J=1.6 Hz, H).

Tert-butylN-[(3R)-6-fluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate,Intermediate FJ

Step a:

A mixture of (3R)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminedihydrochloride (800.0 mg, 2.7 mmol, Intermediate FI),6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (1.03 g, 2.8mmol, Intermediate A) and TEA (1.86 mL, 13.5 mmol) in DMF (25.0 mL) wasstirred at 80° C. for 3 hours. The reaction mixture was cooled to rt andused directly in the next step without further purification. LC-MS(ESI⁺) m/z: 551.0 (M+H)⁺.

Step b:

To a mixture of(3R)-6-fluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine(1.45 g, 2.6 mmol) in DMF (25.0 mL) was added (Boc)₂O (1.20 mL, 5.3mmol), and the mixture was stirred at 15° C. for 2 hours. The mixturewas then diluted with ethyl acetate (70.0 mL), and washed with H₂O (30.0mL×3). The organic phase was washed with brine (20.0 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by silica gel chromatography (ethyl acetate inpetroleum ether, 0% to 40%) to afford tert-butylN-[(3R)-6-fluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(1.30 g, 76% yield) as a white solid. LC-MS (ESI⁺) m/z: 651.1 (M+H)⁺.

6-Chloro-3-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine,Intermediate FK

Step a:

To a mixture of methyl6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate (10.0 g 29.5mmol, Intermediate B) and ammonium persulfate (20.2 g, 88.6 mmol, 19.3mL) in CH₃CN (100 mL) and H₂O (50.0 mL) was added a solution of aceticacid (8.87 g, 148 mmol, 8.45 mL) and AgNO₃ (50.2 g, 295 mmol) in CH₃CN(40.0 mL) and H₂O (20.0 mL) at 70° C. dropwise, then the mixture wasstirred at 70-90° C. for 10 min. Then the mixture was cooled to rt andadjusted to pH=8 with saturated NaHCO₃ solution. The mixture was thenfiltered and the filtrate was extracted with DCM (200 mL×3). Thecombined organic layers were washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to affordmethyl 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate(33.0 g, 65.5 mmol, 55.5% yield) as a yellow solid. LC-MS (ESI⁺) m/z:352.9 (M+H)⁺; ¹HNMR (400 MHz, DMSO): δ 4.07 (s, 3H), 2.75 (s, 3H).

Step b:

To a solution of methyl6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate (28.0g, 55.6 mmol) in DCM (300 mL) was added piperidine (5.21 g, 61.2 mmol,6.04 mL) at 25° C. and the mixture was stirred at 25° C. for 1 h. ThenTsOH.H₂O (13.8 g, 72.3 mmol) and DHP (4.68 g, 55.6 mmol, 5.08 mL) wereadded to the mixture at 25° C. and the mixture was stirred at 25° C. for1 h. The mixture was then washed with saturated NaHCO₃ solution (10.0mL×2) and brine (100 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated and the residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=20:1 to 10:1,R_(f)=0.80) to afford6-chloro-3-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine(11.0 g, 27.2 mmol, 48% yield) as a white solid. LC-MS (ESI⁺) m/z: 379.0(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 5.94 (dd, J₁=2.4 Hz, J₂=10 Hz, 1H),4.14-4.10 (m, 1H), 3.83-3.76 (m, 1H), 2.82 (s, 3H), 2.70-2.59 (m, 1H),2.17-2.13 (m, 1H), 1.99-1.96 (m, 1H), 1.83-1.74 (m, 2H), 1.65-1.63 (m,1H).

Tert-butylN-[(3R)-5-fluoro-1′-[3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate,Intermediate FL

Step a:

A mixture of (R)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-aminedihydrochloride (350.0 mg, 1.2 mmol, Intermediate FD),6-chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (446.0mg, 1.2 mmol, Intermediate FK) and TEA (815.0 μL, 5.9 mmol) in DMF (10.0mL) was stirred at 80° C. for 4 hours. The reaction mixture was thencooled to rt and used directly without further purification in the nextstep. LC-MS (ESI⁺) m/z 565.0 (M+H)⁺.

Step b:

To a mixture of(3R)-5-fluoro-1′-[3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine(650.0 mg, 1.2 mmol) in DMF (10.0 mL) was added (Boc)₂O (527.0 μL, 2.3mmol), and the mixture was stirred at 15° C. for 1 hour. The mixture wasthen diluted with ethyl acetate (40.0 mL), and washed with H₂O (25.0mL×3). The organic phase was washed with brine (15.0 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 25%) to afford tert-butylN-[(3R)-5-fluoro-1′-[3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(520.0 mg, 68% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 665.0 (M+H)⁺.

6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine,Intermediate FM

Step a:

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyridine (350.0 mg, 2.3 mmol,CAS #63725-51-9) in DMF (15.0 mL) was added NIS (764.0 mg, 3.4 mmol),and the resulting mixture was stirred at 110° C. for 12 hours. Thereaction mixture was then quenched with sat. Na₂SO₃ (15.0 mL) and sat.NaHCO₃ (15.0 mL), stirred for 10 min, then H₂O (15.0 mL) was added andthe mixture was stirred for 5 min. The solid was then collected byfiltration, washed with H₂O (50.0 mL) and dried under reduced pressureto afford 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (580.0 mg, 91%yield) as a yellow solid. LC-MS (ESI⁺) m/z 279.8 (M+H)⁺.

Step b:

A mixture of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (580.0 mg, 2.1mmol), DHP (520.0 mg, 6.2 mmol) and CSA (48.0 mg, 207.0 μmol) in DCM(15.0 mL) was stirred at 45° C. for 2 hours. The mixture was then pouredinto sat. NaHCO₃ (40.0 mL), and extracted with DCM (25.0 mL×3). Theorganic phases were washed with brine (20.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (ethyl acetate inpetroleum ether, 0% to 13%) to afford6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyridine (640.0 mg, 85%yield) as a white solid. LC-MS (ESI⁺) m/z 363.8 (M+H)⁺.

Tert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate,Intermediate FN

Step a:

A mixture of tert-butylN-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate (520.0mg, 1.7 mmol, Intermediate EF),6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyridine (621.0 mg, 1.7mmol, Intermediate FM) and TEA (709.0 μL, 5.1 mmol) in DMF (15.0 mL) wasstirred at 90° C. for 18 hours. The mixture was then diluted with ethylacetate (40.0 mL), and washed with H₂O (20.0 mL×3). The organic phasewas washed with brine (10.0 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (ethyl acetate in petroleum ether=0% to 23%)to afford tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(290.0 mg, 27% yield) as a yellow solid. LC-MS (ESI⁺) m/z 630.1 (M+H)⁺.

N-[(3R)-1′-(6-bromopyridin-3-yl)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine,Intermediate FO

Step a:

A mixture of (R)-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-aminedihydrochloride (600.0 mg, 2.0 mmol, Intermediate FI),diphenylmethanimine (329.0 mg, 1.8 mmol) and TEA (841.0 μL, 6.1 mmol) inMeCN (30.0 mL) was stirred at 80° C. for 12 hours. The reaction mixturewas then concentrated under reduced pressure to give a residue, whichwas purified by silica gel chromatography (dichloromethane:methanol=0%to 7%) to afford(R)—N-(diphenylmethylene)-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine(750.0 mg, 96% yield) as a white solid. LC-MS (ESI⁺) m/z: 387.1 (M+H)⁺.

Step b:

A mixture of(R)—N-(diphenylmethylene)-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine(750.0 mg, 1.9 mmol), 3-bromopyridine (458.0 mg, 2.9 mmol), Cs₂CO₃ (1.58g, 4.9 mmol) and XantPhos-Pd-G4 (186.0 mg, 194.0 μmol) in toluene (35.0mL) was stirred at 100° C. for 12 hours under N₂ atmosphere. The mixturewas then concentrated under reduced pressure to give a residue, whichwas purified by silica gel chromatography (ethyl acetate in petroleumether=0% to 65%) to affordN-[(3R)-6-fluoro-1′-(pyridin-3-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine(230.0 mg, 26% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 464.1 (M+H)⁺.

Step c:

To a mixture ofN-[(3R)-6-fluoro-1′-(pyridin-3-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine(230.0 mg, 496.0 μmol) in MeCN (10.0 mL) and DCM (5.0 mL) at 0° C. wasadded NBS (87.7 mg, 496.0 μmol), and the resulting mixture was stirredat 0° C. for 0.5 hours. The mixture was then concentrated under reducedpressure to give a residue, which was purified by silica gelchromatography (ethyl acetate in petroleum ether=0% to 20%) to affordN-[(3R)-1′-(6-bromopyridin-3-yl)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine(230.0 mg, 85.5% yield) as a white solid. LC-MS (ESI⁺) m/z: 544.0(M+H)⁺;

¹HNMR (400 MHz, Methanol-d₄): δ 7.96 (d, J=3.2 Hz, 1H), 7.57-7.55 (m,2H), 7.47-7.39 (m, 3H), 7.35-7.30 (m, 1H), 7.27-7.21 (m, 3H), 7.16-7.12(m, 2H), 7.04-7.01 (m, 1H), 6.92-6.86 (m, 1H), 6.53-6.46 (m, 2H), 4.67(s, 1H), 3.46-3.41 (m, 1H), 3.29-3.12 (m, 3H), 2.32-2.28 (m, 1H),1.98-1.90 (m, 1H), 1.74-1.69 (m, 1H), 1.59-1.54 (m, 1H).

N-[(3R)-1′-(6-bromopyridin-3-yl)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine,Intermediate FP

Step a:

To a solution of(3R)-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine (500.0 mg,2.2 mmol, Intermediate FD) in MeCN (5.00 mL) was added TEA (678.0 mg,6.7 mmol), and the reaction mixture was stirred at 95° C. for 1 hour. Tothe reaction mixture was next added diphenylmethanimine (405.0 mg, 2.24mmol) and the reaction was stirred for 10 hours at 95° C. The reactionmixture was then concentrated and the residue was purified by silica gelchromatography (DCM/MeOH=30/1 to 8/1) to afford(R)—N-(diphenylmethylene)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-amine(600 mg, 69% yield) as a white solid. LC-MS (ESI⁺) m/z: 387.0 (M+H)⁺.

Step b:

A mixture ofN-[(3R)-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine(600.0 mg, 1.5 mmol), Pd₂(dba)₃ (141.0 mg, 0.15 mmol), t-BuONa (446.0mg, 4.65 mmol), 3-bromopyridine (489.0 mg, 3.1 mmol) and BINAP (193.0mg, 0.3 mmol) in toluene (5.00 mL) was stirred at 100° C. for 12 hoursunder N₂ atmosphere. The mixture was then concentrated to give a residuewhich was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 70%) to affordN-[(3R)-5-fluoro-1′-(pyridin-3-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine(700.0 mg, 97% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 464.1 (M+H)⁺.

Step c:

To a mixture ofN-[(3R)-6-fluoro-1′-(pyridin-3-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine(300.0 mg, 0.6 mmol) in MeCN (5.00 mL) and DCM (2.50 mL) was added NBS(114.0 mg, 0.6 mmol) at 0° C., and the resulting mixture was stirred at0° C. for 0.5 hour. The reaction mixture was then concentrated andpurified by silica gel chromatography (petroleum ether/EtOAc=30/1 to1/1) to affordN-[(3R)-1′-(6-bromopyridin-3-yl)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-1,1-diphenylmethanimine(330.0 mg, 94% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 544.1 (M+H)⁺.

tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate,Intermediate FO

Step a:

A mixture of 2,5-dibromopyrazine (200.0 mg, 0.8 mmol, CAS #23229-25-6),(3R)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminedihydrochloride (272.0 mg, 0.9 mmol, Intermediate FI) and TEA (580 μL,4.2 mmol) in DMF (10 mL) was stirred at 80° C. for 2 hours. The solutionwas cooled to rt and used into the next step directly. LC-MS (ESI⁺) m/z:361.8 (M−NH₂)⁺.

Step b:

To the solution of(3R)-1′-(5-bromopyrazin-2-yl)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine(318.0 mg, 0.8 mmol) in DMF (10 mL) was added di-tert-butyl dicarbonate(383 μL, 1.7 mmol) at 15° C., and the reaction mixture was stirred at15° C. for 12 hours. The reaction mixture was then diluted with water(30 mL), and extracted with EtOAc (50 mL×2). The organic layers werewashed with H₂O (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (20 g column, EtOAc in petroleum ether from 0%˜10%) togive tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(260.0 mg, 0.5 mmol, 65% yield over two steps) as a yellow solid. LC-MS(ESI⁺) m/z: 478.9 (M+H)⁺.

tert-butylN-[(3R)-6-fluoro-1′-(5-sulfanylpyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate,Intermediate FR

Step a:

A mixture of (R)-tert-butyl(1′-(5-bromopyrazin-2-yl)-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamate(260.0 mg, 0.5 mmol, Intermediate FQ), 2-ethylhexyl 3-sulfanylpropanoate(130.0 mg, 0.6 mmol, CAS #50448-95-8), Pd₂(dba)₃ (49.6 mg, 0.05 mmol),XantPhos (62.7 mg, 0.11 mmol) and DIPEA (265 μL, 1.6 mmol) in dioxane(10 mL) was stirred at 100° C. for 12 hours under N₂ atmosphere. Thereaction mixture was then poured into H₂O (20 mL) and extracted withEtOAc (40 mL×2). The combined organic layers were washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography (ethyl acetate in petroleum ether=0% to 15%) toafford 2-ethylhexyl3-({5-[(3R)-3-{[(tert-butoxy)carbonyl]amino}-6-fluoro-3H-spiro[1-benzofuran-2,4(190.0 mg, 0.3 mmol, 57% yield) as a yellow solid. LC-MS (ESI⁺) m/z:617.2 (M+H)⁺.

Step b:

To the mixture of 2-ethylhexyl3-({5-[(3R)-3-{[(tert-butoxy)carbonyl]amino}-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)propanoate(188.0 mg, 0.3 mmol) in anhydrous THE (1.5 mL) was added t-BuOK (0.9 mL,0.9 mmol, 1 M in THF) during 10 min at −78° C., and the resultingmixture was stirred at −78° C. for 0.5 hour under N₂ atmosphere. Thereaction mixture was diluted with DCM (30 mL) and acidified withHCl/EtOAc (2 N, 1 mL) to pH=6 at −78° C. The mixture was then washedwith H₂O (20 mL) and brine (20 ml). The organic layer were dried overanhydrous Na₂SO₄, filtered and concentrated to give tert-butylN-[(3R)-6-fluoro-1′-(5-sulfanylpyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(131.0 mg, 100% crude yield) as a red oil.

(1s,4s)-4-(6-sulfanylpyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one,Intermediate FS

Step a:

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carbonitrile(4.5 g, 19.3 mmol, CAS #1310384-20-3), 5-bromo-2-methoxypyridine (4.0 g,21.2 mmol, CAS #13472-85-0), K₂CO₃ (5.3 g, 38.6 mmol) and Pd(dppf)Cl₂(1.4 g, 1.9 mmol) were placed into dioxane (300 mL) and H₂O (30 mL). Thereaction mixture was evacuated and refilled 3 times using N₂, and thereaction mixture was stirred at 100° C. for 12 hours. The reactionmixture was then concentrated and H₂O (100 mL) was added, and themixture was extracted with EtOAc (150 mL×3). The combined organic layerswere washed with brine (50 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:30) to afford 4-(6-methoxypyridin-3-yl)cyclohex-3-ene-1-carbonitrile(3.8 g, 17.7 mmol, 92% yield) as a white solid. LC-MS (ESI⁺) m/z: 215.1(M+H)⁺.

Step b:

4-(6-Methoxypyridin-3-yl)cyclohex-3-ene-1-carbonitrile (1.9 g, 8.9 mmol)and 1-bromo-2-(bromomethyl)benzene (2.4 g, 9.7 mmol, CAS #3433-80-5)were dissolved in THE (200 mL). Then LDA (4.9 mL, 9.7 mmol, 2 M in THF)was added dropwise into the mixture at −10° C. The mixture was stirredat 0° C. for 0.5 hour, then the mixture was then warmed to 25° C. for 1hour. Additional LDA (4.4 mL, 8.9 mmol, 2 M in THF) was added dropwiseinto the mixture at −10° C. The mixture was stirred at 0° C. for 0.5hour, then mixture was then warmed to 25° C. for 1 hour. The combinedreaction mixture was quenched by addition of sat. NH₄Cl (100 mL). Themixture was then extracted with ethyl acetate (200 mL×3). The combinedorganic layers were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (petroleum ether:ethylacetate=100:0 to 100:20) to afford1-[(2-bromophenyl)methyl]-4-(6-methoxypyridin-3-yl)cyclohex-3-ene-1-carbonitrile(3.3 g, combined product) as a yellow oil.

Step c:

1-[(2-Bromophenyl)methyl]-4-(6-methoxypyridin-3-yl)cyclohex-3-ene-1-carbonitrile(3.3 g, 8.6 mmol), PdCl₂(AmPhos)₂ (304.0 mg, 0.4 mmol, CAS #887919-35-9)and TEA (4.8 mL, 34.4 mmol) were placed into DMA (60 mL) and H₂O (1.2mL). The reaction mixture was evacuated and refilled 3 times using N₂,and the reaction mixture was stirred at 120° C. for 12 hours. Themixture was concentrated to give a residue, which was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:20) to afford 4-(6-methoxypyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one (2.3 g, 88% yield)as a yellow solid. LC-MS (ESI+) m/z: 306.2 (M+H)⁺.

Step d:

4-(6-Methoxypyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one(2.3 g, 7.5 mmol) was dissolved in MeOH (100 mL) and THE (6 mL). Then10% Pd/C (300.0 mg, wet) was added and the reaction mixture wasevacuated and refilled 3 times using H₂. The reaction mixture was thenstirred at 25° C. for 12 hours under H₂ (50 psi). The mixture was thenfiltered and the filtrate was concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (80 g, ethylacetate/petroleum ether=0/100 to 18/100) to(1s,4s)-4-(6-methoxypyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(1.02 g, 3.3 mmol, 44% yield) as a yellow solid (LC-MS (ESI+) m/z: 307.9(M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.73 (d, J=7.6 Hz, 1H),7.65-7.56 (m, 2H), 7.42-7.37 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 3.93 (s,3H), 2.99 (s, 2H), 2.61-2.59 (m, 1H), 2.40-2.30 (m, 2H), 1.97 (br d,J=12.4 Hz, 2H), 1.73-1.68 (m, 4H) and(1r,4r)-4-(6-methoxypyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(0.7 g, 2.3 mmol, 30% yield) as a yellow solid. LC-MS (ESI+) m/z: 307.9(M+H)⁺.

Step e:

TMSI (7.1 mL, 49.6 mmol) was added to a mixture of(1s,4s)-4-(6-methoxypyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(1.02 g, 3.3 mmol) in DCM (70 mL). The mixture was stirred at 50° C. for12 hours. The mixture was then diluted with DCM (80 mL) and H₂O (30 mL)was added. The partitioned layers were separated and the aqueous phasewas extracted with DCM (40 mL×2). The combined organic layers werewashed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was triturated with theEtOAc (5 mL) where precipitate formed, and the solid was collected byfiltration. The filter cake was washed with EtOAc (1 mL), and dried togive(1s,4s)-4-(6-hydroxypyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(900.0 mg, 3.1 mmol, 93% yield) as a yellow solid. LC-MS (ESI⁺) m/z:293.9 (M+H)⁺.

Step f:

(1s,4s)-4-(6-Hydroxypyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(800.0 mg, 2.7 mmol) and TEA (5.6 mL, 40.8 mmol) were dissolved in theDCM (35 mL) and Tf₂O (3.2 mL, 19.0 mmol) was added. The mixture wasstirred at 20° C. for 2 hours. Then the mixture was diluted with DCM (60mL), washed with H₂O (40 mL) and brine (15 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (ethyl acetate/petroleumether=0/100 to 20/100) to give5-[(1s,4s)-3′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-yl]pyridin-2-yltrifluoromethanesulfonate (1.02 g, 2.4 mmol, 89% yield) as a yellowsolid. LC-MS (ESI⁺) m/z: 426.0 (M+H)⁺.

Step g:

5-[(1s,4s)-3′-Oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-yl]pyridin-2-yltrifluoromethanesulfonate (900.0 mg, 2.1 mmol), 2-ethylhexyl3-sulfanylpropanoate (506.0 mg, 2.3 mmol), XantPhos (244.0 mg, 0.4mmol), Pd₂(dba)₃ (193.0 mg, 0.2 mmol), and DIPEA (1.1 mL, 6.3 mol) wereadded into dioxane (30 mL). The reaction mixture was evacuated andrefilled 3 times using N₂, and the solution was stirred at 100° C. for12 hours. The reaction mixture was then diluted with DCM (50 mL),filtered and concentrated to give a residue. The residue was purified byflash column chromatography (40 g column, petroleum ether/EtOAc=100:0 to100:10) to afford 2-ethylhexyl3-((5-((1s,4s)-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-yl)pyridin-2-yl)thio)propanoate(1.45 g, 2.9 mmol, combined product) as a yellow oil. LC-MS (ESI+) m/z:494.2 (M+H)⁺.

Step h:

2-Ethylhexyl3-((5-((1s,4s)-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-yl)pyridin-2-yl)thio)propanoate(500.0 mg, 1.0 mmol) was dissolved in THE (6 mL). The reaction mixturewas cooled to −78° C. and t-BuOK (3.0 mL, 1 M in THF) was added dropwiseover 10 min under N₂. The reaction mixture was stirred at −78° C. for 30min. Then the reaction mixture was diluted with DCM (50 mL) andacidified with HCl/MeOH (2 N) to pH=5-6 at −78° C. The mixture waswashed with H₂O (30 mL×3) and brine (20 ml). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated to give(1s,4s)-4-(6-sulfanylpyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(312.0 mg, 100% crude yield) as a yellow solid.

Tert-butylN-[(3S)-1′-(1-benzyl-6-oxo-5-sulfanyl-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate,Intermediate FT

Step a:

A mixture of tert-butylN-[(3S)-1′-(1-benzyl-5-iodo-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(400.0 mg, 0.6 mmol, Intermediate FC), Pd₂(dba)₃ (59.7 mg, 0.06 mmol),DIPEA (247.0 mg, 1.9 mmol), XantPhos (75.5 mg, 0.1 mmol), and2-ethylhexyl 3-mercaptopropanoate (283.0 mg, 1.3 mmol) in 1,4-dioxane(10.00 mL) was stirred at 100° C. for 12 hours under N₂ atmosphere. Themixture was then concentrated in vacuo to give a residue, which waspurified by silica gel chromatography (ethyl acetate in petroleumether=0% to 85%) to afford 2-ethylhexyl3-({1-benzyl-2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-oxo-1,6-dihydropyrimidin-5-yl}sulfanyl)propanoate(400.0 mg, 83% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 703.4 (M+H)⁺.

Step b:

2-Ethylhexyl3-({1-benzyl-2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-oxo-1,6-dihydropyrimidin-5-yl}sulfanyl)propanoate(400.0 mg, 0.5 mmol) was dissolved in THE (6.00 mL). The reactionmixture was cooled to −78° C. and t-BuOK (3.03 mL, 1 M in THF) was addeddropwise under N₂. The reaction mixture was stirred at −78° C. for 60min. Then the reaction mixture was diluted with DCM (50 mL) andacidified with HCl/MeOH (2 N) to pH=5-6 at −78° C. The mixture waswashed with H₂O (30 mL×3) and brine (20 ml). The organic layer weredried over anhydrous Na₂SO₄, filtered and concentrated to givetert-butylN-[(3S)-1′-(1-benzyl-6-oxo-5-sulfanyl-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(280.0 mg, 95% crude yield) as a yellow solid. LC-MS (ESI⁺) m/z: 519.1(M+H)⁺.

(10R)-5-bromo-8-oxa-1,3,6-triazatricyclo[8.4.0.0²,⁷]tetradeca-2(7),3,5-trien-12-one,Intermediate FU

Step a:

To the stirred solution of(R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (90.0 g,370 mmol) in DMF (450 mL) was added Cs₂CO₃ (133 g, 407 mmol) and themixture was stirred at 20° C. for 10 minutes. Then CH₃I (78.2 g, 551mmol, 34.3 mL) was added to the mixture dropwise and the reactionmixture was stirred at 20° C. for 2 h. The reaction mixture was filteredand the filter cake was washed with ethyl acetate (500 mL). The filtratewas poured into H₂O (2.00 L) and extracted with ethyl acetate (500mL×2). The combined organic layers were washed with brine (500 mL×2),dried over Na₂SO₄, filtered and concentrated to give 1-(tert-butyl)2-methyl (R)-4-oxopiperidine-1,2-dicarboxylate (92.0 g, 88% crude yield)as a yellow oil. ¹HNMR (400 MHz, CDCl₃): δ 5.13-4.85 (m, 1H), 4.11-4.04(m, 1H), 3.75-3.56 (m, 4H), 2.78 (s, 2H), 2.51 (s, 2H), 1.47 (s, 9H).

Step b:

To the stirred solution of 1-(tert-butyl) 2-methyl(R)-4-oxopiperidine-1,2-dicarboxylate (92.0 g, 358 mmol) in DCM (230 mL)was added TFA (354 g, 3.11 mol, 230 mL) at 20° C. and the mixture wasstirred at 20° C. for 2 h. The reaction mixture was then concentrated togive methyl (R)-4-oxopiperidine-2-carboxylate (97.0 g, quant. crudeyield, TFA) as a yellow oil. ¹HNMR (400 MHz, MeOD): δ 4.21-4.12 (m, 1H),3.85 (s, 3H), 3.46-3.39 (m, 1H), 3.21-3.08 (m, 1H), 2.45-2.37 (m, 1H),2.15-2.01 (m, 1H), 1.95-1.76 (m, 2H).

Step c:

To the stirred solution of methyl (R)-4-oxopiperidine-2-carboxylate(80.0 g, 295 mmol, TFA) and TEA (149 g, 1.47 mol, 205 mL) in DCM (400mL) was added CbzCl (75.5 g, 442 mmol, 62.9 mL) at 0° C. Then thereaction was stirred at 15° C. for 12 h. Next, CbzCl (30.0 mL) was addedat 0° C. and the reaction mixture was stirred at 15° C. for 2 h. To thereaction mixture was then added H₂O (1.00 L) and the mixture wasextracted with DCM (500 mL×3). The combined organic layers were washedwith brine (500 mL×3), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (petroleum ether/ethylacetate=1/0˜2/1) (petroleum ether/ethyl acetate=2/1, R_(f)=0.60) to give1-benzyl 2-methyl (R)-4-oxopiperidine-1,2-dicarboxylate (46.0 g, 153mmol, 50% yield over 3 steps) as a yellow oil. LC-MS (ESI⁺) m/z: 291.9(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.38-7.36 (m, 5H), 5.24-5.02 (m, 3H),4.17-4.13 (m, 1H), 3.76-3.66 (m, 4H), 2.90-2.74 (m, 2H), 2.55-2.51 (m,2H)

Step d:

A solution of 1-benzyl 2-methyl (R)-4-oxopiperidine-1,2-dicarboxylate(41.0 g, 141 mmol), ethane-1,2-diol (34.9 g, 563 mmol, 31.5 mL) and4-methylbenzenesulfonic acid; hydrate (2.68 g, 14.1 mmol) in toluene(205 mL) was heated to 110° C. and stirred at 110° C. for 2 h withDean-Stark trap removal of water. The reaction mixture was poured intosaturated NaHCO₃ aqueous (500 mL) and extracted with ethyl acetate (300mL×2). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give 8-benzyl 7-methyl(R)-1,4-dioxa-8-azaspiro[4.5]decane-7,8-dicarboxylate (47.2 g, quant.crude yield) as a yellow oil. ¹HNMR (400 MHz, CDCl₃): δ 7.38-7.28 (m,5H), 5.18-5.11 (m, 2H), 5.06-4.92 (m, 1H), 4.25-4.12 (m, 1H), 4.02-3.87(m, 4H), 3.75-3.70 (m, 3H), 3.46-3.32 (m, 1H), 2.45-2.36 (m, 2H),1.89-1.64 (m, 2H).

Step e:

To the stirred solution of 8-benzyl 7-methyl(R)-1,4-dioxa-8-azaspiro[4.5]decane-7,8-dicarboxylate (48.0 g, 143 mmol)in THE (480 mL) was added LAH (10.9 g, 286 mmol) in portions at 0° C.under N₂. The reaction mixture was stirred at 20° C. for 2 h. Thereaction mixture was then quenched with H₂O (10.9 mL) at 10° C., then15% NaOH aqueous (10.9 mL) and Na₂SO₄ solid (50.0 g) were added. Theresulting mixture was stirred at 20° C. for 0.5 h. The mixture was thenfiltered and the filter cake was washed with ethyl acetate (500 mL×2),and the filtrate was concentrated to give benzyl(R)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate(38.2 g, 87% crude yield) as a light yellow oil. ¹HNMR (400 MHz, CDCl₃):δ 7.38-7.29 (m, 5H), 4.70 (s, 2H), 3.99-3.94 (m, 4H), 3.85 (dd, J=11.6,4.0 Hz, 1H), 3.38 (dd, J=11.2, 2.0 Hz, 1H), 2.90-2.84 (m, 1H), 2.50-2.43(m, 1H), 2.31-2.27 (m, 1H), 1.95-1.88 (m, 1H), 1.80 (td, J=12.8, 4.4 Hz,1H), 1.69-1.63 (m, 2H).

Step f:

To the stirred solution of benzyl(R)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate(41.0 g, 133 mmol) in MeOH (410 mL) was added Pd/C (4.10 g, 10 wt %)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (50 psi) at 15° C. for14 h. The reaction mixture was then filtered and the filtrate was addedPd/C (5.00 g, 10 wt) under N₂. The suspension was degassed under vacuumand purged with H₂ several times. The mixture was again stirred under H₂(50 psi) at 40° C. for 4 h. The reaction mixture was filtered and thefiltrate was concentrated. The residue was dissolved in MeOH (400 mL)and added Pd/C (5.00 g, 10 wt %) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (50 psi) at 50° C. for 20 h. Finally, Pd(OH)₂ (5.00 g, 20 wt %)was added under N₂. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred under H₂ (50 psi) at 50°C. for 20 h. The reaction mixture was filtered and the filtrate wasconcentrated to give (R)-(1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol(25.0 g, quant. crude yield) as a yellow oil. ¹HNMR (400 MHz, MeOD): δ3.96-3.93 (m, 4H), 3.61-3.59 (m, 2H), 2.89-2.85 (m, 1H), 2.53-2.47 (m,1H), 2.37-2.32 (m, 1H), 1.81-1.76 (m, 2H), 1.71-1.67 (m, 2H).

Step g:

To a solution of (R)-(1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol (16.5g, 95.3 mmol) and CsF (43.4 g, 286 mmol, 10.5 mL) in DMSO (120 mL) wasadded 2,3-dibromopyrazine (22.7 g, 95.3 mmol). The mixture was stirredat 130° C. for 2.5 h. The reaction mixture was then diluted with H₂O(500 mL) and extracted with ethyl acetate (300 mL×3). The combinedorganic layers were washed with brine (200 mL×2), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether/ethyl acetate=50/1˜1/2, R_(f)=0.20) to give(R)-6a,7,9,10-tetrahydro-6H-spiro[pyrazino[2,3-b]pyrido[1,2-d][1,4]oxazine-8,2′-[1,3]dioxolane](7.90 g, 29.5 mmol, 26% yield over 4 steps) as a yellow oil. LC-MS(ESI⁺) m/z: 250.1 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.71 (d, J=2.8 Hz,1H), 7.45 (d, J=2.8 Hz, 1H), 4.64-4.60 (m, 1H), 4.39 (dd, J=11.2, 2.8Hz, 1H), 4.14-4.10 (m, 1H), 4.01 (s, 4H), 3.62-3.56 (m, 1H), 3.00-2.93(m, 1H), 1.85-1.75 (m, 3H), 1.61-1.58 (m, 1H).

Step h:

To the stirred solution of(R)-6a,7,9,10-tetrahydro-6H-spiro[pyrazino[2,3-b]pyrido[1,2-d][1,4]oxazine-8,2′-[1,3]dioxolane](7.90 g, 29.5 mmol) in DCM (79.0 mL) was added NBS (5.25 g, 29.5 mmol).The mixture was stirred at 15° C. for 0.5 h. The reaction mixture wasthen washed with brine (50.0 mL×2). The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was triturated with 100mL of petroleum ether/ethyl acetate (20/1) at 15° C. for 15 mins. Thesuspension was filtered, the cake was dried under reduced pressure togive(R)-3-bromo-6a,7,9,10-tetrahydro-6H-spiro[pyrazino[2,3-b]pyrido[1,2-d][1,4]oxazine-8,2′-[1,3]dioxolane](9.40 g, 28.6 mmol, 97% yield) as a yellow solid. LC-MS (ESI⁺) m/z:328.0 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.80 (s, 1H), 4.55-4.38 (m, 1H),4.40 (dd, J=11.6, 3.2 Hz, 1H), 4.12 (dd, J=11.2, 7.6 Hz, 1H), 4.02-3.99(m, 4H), 3.60-3.57 (m, 1H), 3.00-2.92 (m, 1H), 1.84-1.75 (m, 3H),1.60-1.53 (m, 1H).

Step i:

To the stirred solution of give(R)-3-bromo-6a,7,9,10-tetrahydro-6H-spiro[pyrazino[2,3-b]pyrido[1,2-d][1,4]oxazine-8,2′-[1,3]dioxolane](8.80 g, 26.8 mmol) was added HCOOH (1.29 g, 26.8 mmol, 44.0 mL) at 15°C. The solution was then stirred at 40° C. for 4 h. The reaction mixturewas then concentrated. The residue was purified by column chromatography(SiO₂, petroleum ether/ethyl acetate=6/1˜2/1, R_(f)=0.30) to give(R)-3-bromo-6a,7,9,10-tetrahydropyrazino[2,3-b]pyrido[1,2-d][1,4]oxazin-8(6H)-one(7.07 g, 24.0 mmol, 90% yield) as a yellow gum. LC-MS (ESI⁺) m/z: 284.0(M+H)⁺; ¹HNMR (400 MHz, CDCl₃): δ 7.87 (s, 1H), 4.87-4.82 (m, 1H), 4.53(dd, J=11.6, 3.2 Hz, 1H), 4.22 (dd, J=11.6, 6.0 Hz, 1H), 3.81-3.75 (m,1H), 3.21-3.18 (m, 1H), 2.60-2.46 (m, 4H).

N-[(3R,7′R)-12′-bromo-3H-9′-oxa-2′,11′,14′-triazaspiro[1-benzofuran-2,5′-tricyclo[8.4.0.0²,⁷]tetradecane]-1′(10′),11′,13′-trien-3-yl]-2-methylpropane-2-sulfinamide,Intermediate FV

Step a:

To a solution of 2-(2-fluorophenyl)-1,3-dithiane (900.0 mg, 4.19 mmol,synthesized via Step a of Intermediate AP) in THF (20.0 mL) was addedLDA (2.19 mL, 4.39 mmol, 2 M) at −78° C. under N₂. The reaction mixturewas stirred at −78° C. for 0.5 hour, then(10R)-5-bromo-8-oxa-1,3,6-triazatricyclo[8.4.0.0²,⁷]tetradeca-2(7),3,5-trien-12-one(600.0 mg, 2.11 mmol, Intermediate FU) in THE (10.0 mL) was added at−78° C. The reaction mixture was then stirred at 10° C. for 11.5 hoursunder N₂. The reaction mixture was then poured into H₂O (100.0 mL) andextracted with EtOAc (100.0 mL×2). The combined layers were concentratedand the residue was triturated with EtOAc:petroleum ether=1:1 to give(10R)-5-bromo-12-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-8-oxa-1,3,6-triazatricyclo[8.4.0.0²,⁷]tetradeca-2(7),3,5-trien-12-ol(700.0 mg, 67.3% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 497.9 and499.9 (M+H)⁺.

Step b:

To a solution of(10R)-5-bromo-12-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-8-oxa-1,3,6-triazatricyclo[8.4.0.0²,⁷]tetradeca-2(7),3,5-trien-12-ol(700.0 mg, 1.40 mmol) in DCM/H₂O (30.0 mL/3.0 mL) was added pyridine(0.5 mL), Pyr.HBr₃ (668.0 mg, 2.09 mmol) and TBAB (90.2 mg, 280.0 μmol)at 25° C. The reaction mixture was stirred at 25° C. for 12 hours. Thenthe reaction mixture was poured into H₂O (100.0 mL) and extracted withDCM (100.0 mL×2). The combined organic layers were washed with brine(200.0 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (20 g column, ethyl acetatein petroleum ether from 0% to 35%) to give(10R)-5-bromo-12-(2-fluorobenzoyl)-8-oxa-1,3,6-triazatricyclo[8.4.0.0²,⁷]tetradeca-2(7),3,5-trien-12-ol(530.0 mg, 93% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 407.9 and 409.9(M+H)⁺.

Step c:

A solution of(10R)-5-bromo-12-(2-fluorobenzoyl)-8-oxa-1,3,6-triazatricyclo[8.4.0.0²,⁷]tetradeca-2(7),3,5-trien-12-ol(500.0 mg, 1.22 mmol) and t-BuOK (341.0 mg, 3.05 mmol) in dioxane (15.0mL) was stirred at 70° C. for 2 hours. The reaction mixture was pouredinto H₂O (100.0 mL) and extracted with EtOAc (100.0 mL×2). The combinedorganic layers were washed with brine (200.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash silica gel chromatography (20g column, ethyl acetate in petroleum ether from 0% to 25%) to give(7′R)-12′-bromo-3H-9′-oxa-2′,11′,14′-triazaspiro[1-benzofuran-2,5′-tricyclo[8.4.0.0²,⁷]tetradecane]-1′(10′),11′,13′-trien-3-one(210.0 mg, 44% yield) as a white solid. LC-MS (ESI⁺) m/z: 387.9 and389.9 (M+H)⁺.

Step d:

To a solution of(7′R)-12′-bromo-3H-9′-oxa-2′,11′,14′-triazaspiro[1-benzofuran-2,5′-tricyclo[8.4.0.0²,⁷]tetradecane]-1′(10′),11′,13′-trien-3-one(210.0 mg, 0.54 mmol) and Ti(OEt)₄ (492.0 mg, 2.16 mmol) in 2-Me-THF(15.0 mL) was added (R)-2-methylpropane-2-sulfinamide (130.0 mg, 1.08mmol). The reaction mixture was stirred at 90° C. for 12 hours under N₂.The reaction mixture was cooled to rt and used in the next step withoutfurther purification. LC-MS (ESI⁺) m/z: 491.0 and 493.0 (M+H)⁺.

Step e:

To a solution ofN-[(7′R)-12′-bromo-3H-9′-oxa-2′,11′,14′-triazaspiro[1-benzofuran-2,5′-tricyclo[8.4.0.0²,⁷]tetradecane]-1′(10′),11′,13′-trien-3-ylidene]-2-methylpropane-2-sulfinamide(270.0 mg, 0.55 mmol) in 2-Me-THF (15.0 mL) was added LiBH₄ (23.7 mg,1.09 mmol) at −78° C. and the reaction mixture was stirred at −78° C.for 2 hours. The reaction mixture was then poured into H₂O (100.0 mL)and extracted with EtOAc (100.0 mL×2). The combined organic layers werewashed with brine (200.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (4 g, ethyl acetate inpetroleum ether from 0% to 50%) to giveN-[(3R,7′R)-12′-bromo-3H-9′-oxa-2′,11′,14′-triazaspiro[1-benzofuran-2,5′-tricyclo[8.4.0.0²,⁷]tetradecane]-1′(10′),11′,13′-trien-3-yl]-2-methylpropane-2-sulfinamide(250.0 mg, 92% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 493.0 and 495.0(M+H)⁺.

(S)—N—((S)-1′-(2-bromothiazole-4-carbonyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide,Intermediate FW

Step a:

2-Bromo-1,3-thiazole-4-carboxylic acid (200.0 mg, 961 μmol), TEA (671μL, 4.80 mmol), HATU (547.0 mg, 1.44 mmol) and(R)—N—((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(352.0 mg, 1.15 μmol, synthesized via Step a of Example 120) were placedinto DMF (15 mL). The reaction mixture was evacuated and refilled 3times using N₂, and the reaction mixture was stirred at 25° C. for 1hour. The mixture was then diluted with EtOAc (100 mL) and the mixturewas washed with H₂O (30 mL×5), brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by silica gel chromatography (ethyl acetate in petroleumether=0% to 80%) to afford(S)—N—((S)-1′-(2-bromothiazole-4-carbonyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(458 mg, 96% yield) as yellow oil. LC-MS (ESI+) m/z: 498.0 (M+H)⁺.

1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic Acid, Intermediate FX1-(3-methoxyphenyl)-1H-pyrazole-5-carboxylic Acid, Intermediate FY

Step a:

A mixture of methyl 1H-pyrazole-3-carboxylate (500.0 mg, 3.96 mmol),3-methoxyphenyl boronic acid (901.0 mg, 5.9 mmol), Cu(OAc)₂ (1.43 g, 7.9mmol) and TEA (2.7 mL, 19.7 mmol) in DCM (15 mL) was stirred at 40° C.for 12 h under O₂ atmosphere. The reaction mixture was then filtered.The filtrate was concentrated, and the residue was purified by flashsilica gel chromatography (80 g column, EtOAc in petroleum ether from0%˜30%) to give methyl 1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate(190 mg, 21% yield, the higher polarity) as a yellow oil (LC-MS (ESI⁺)m/z: 232.9 (M+H)⁺) and methyl1-(3-methoxyphenyl)-1H-pyrazole-5-carboxylate (30.0 mg, 3% yield) as ayellow solid (LC-MS (ESI⁺) m/z: 232.9 (M+H)⁺).

Step b:

To a mixture of methyl 1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate(190.0 mg, 0.82 mmol) in MeOH (3.00 mL) was added NaOH (327 mg, 8.18mmol) in H₂O (2 mL). The reaction mixture was then stirred at 60° C. for1 hour. The reaction mixture was then concentrated and quenched withwater (10 mL). The mixture was adjusted to pH=5-6 with diluted HCl (1.2M), where precipitate formed. The solid was collected by filtration, anddried in vacuo to give 1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic acid(95.0 mg, 53% yield) as an off-white solid. LC-MS (ESI⁺) m/z: 218.9(M+H)⁺.

Step c:

To the reaction mixture of methyl1-(3-methoxyphenyl)-1H-pyrazole-5-carboxylate (30 mg, 0.13 mmol) in MeOH(1.00 mL) was added NaOH (51.5 mg, 1.29 mmol) in H₂O (1 mL). Thereaction mixture was stirred at 60° C. for 1 hour. Then the reactionmixture was concentrated, and quenched with water (10 mL). The mixturewas adjusted to pH=5-6 with diluted HCl solution (1.2 M), whereprecipitate formed. The reaction mixture was extracted with EtOAc (20mL×2). The organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to give 1-(3-methoxyphenyl)-1H-pyrazole-5-carboxylic acid(28.1 mg, 0.13 mmol, quant. crude yield) as a white solid. LC-MS (ESI⁺)m/z: 218.9 (M+H)⁺.

1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxylic Acid,Intermediate FZ

Step a:

To a mixture of ethyl 2,4-dioxopentanoate (1.00 g, 6.3 mmol) in EtOH(25.0 mL) was added (2,4-difluorophenyl)hydrazine hydrochloride (1.25 g,7.0 mmol) and AcOH (2.52 mL, 44.2 mmol), and the resulting mixture wasstirred at 60° C. for 12 hours. The mixture was concentrated in vacuo togive a residue, which was dissolved in ethyl acetate (30.0 mL), andwashed with sat. NaHCO₃ (20.0 mL×2). The organic phase was washed withbrine (10.0 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give a residue, which was purified by silica gelchromatography (ethyl acetate in petroleum ether=0% to 25%) to affordethyl 1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxylate (1.00 g,60% yield) as a yellow solid. LC-MS (ESI⁺) m/z 266.9 (M+H)⁺; ¹HNMR (400MHz, CDCl3): δ 7.51-7.47 (m, 1H), 7.05-7.00 (m, 2H), 6.76 (s, 1H),4.46-4.40 (m, 2H), 2.24 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).

Step b:

A mixture of ethyl1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxylate (400.0 mg, 1.5mmol) and LiOH H₂O (315.0 mg, 7.5 mmol) in MeOH (20.0 mL) and H₂O (8.0mL) was stirred at 20° C. for 12 hours. The reaction mixture wasconcentrated in vacuo to give a residue, which was dissolved in H₂O(25.0 mL) and adjusted to pH=4 with 2M HCl. The mixture was thenextracted with ethyl acetate (30.0 mL×2), and the organic phases werewashed with brine (20.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (310 mg,86.8% yield) as a yellow solid. LC-MS (ESI⁺) m/z 239.0 (M+H)⁺.

2′-Chloro-3′, 6′-dimethyl-3,4′-bipyridine, Intermediate GA

Step a:

A mixture of 2, 4-dichloro-3,6-dimethylpyridine (300.0 mg, 1.7 mmol, CAS#83791-90-6), (pyridin-3-yl)boronic acid (271.0 mg, 2.2 mmol, CAS#1692-25-7), Pd(dppf)Cl₂ (124.0 mg, 0.2 mmol), K₂CO₃ (715.0 mg, 5.1mmol) were added in dioxane (6 mL) and H₂O (2 mL). The reaction mixturewas evacuated and refilled 3 times using N₂, and the reaction mixturewas stirred at 100° C. for 12 hours. The reaction mixture was pouredinto H₂O (20 mL) and extracted with EtOAc (40 mL×2). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash silica gel chromatography (20g column, EtOAc in petroleum ether from 0% to 50%) to give 2′-chloro-3′,6′-dimethyl-3,4′-bipyridine (270.0 mg, 1.2 mmol, 73% yield) as a brownsolid. LC-MS (ESI+) m/z: 218.9 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 9.36 (s,1H), 9.18 (d, J=5.6 Hz, 1H), 8.98 (d, J=8.0 Hz, 1H), 8.40-8.37 (m, 1H),8.18 (s, 1H), 2.83 (s, 3H), 2.46 (s, 3H).

Examples Method 1, Example 1 & 2: Synthesis of1-(4-{6-[(3R)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinoxalin-1-yl)ethan-1-one(RTX-1084025) and(1-(4-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinoxalin-1-yl)ethan-1-one

Step a:

A mixture of tert-butylN-{1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(150.0 mg, 237.0 μmol, Intermediate F),1-(1,2,3,4-tetrahydroquinoxalin-1-yl)ethan-1-one (50.0 mg, 284.0 μmol,Intermediate L), XantPhos-Pd-G4 (22.7 mg, 23.7 μmol) and Cs₂CO₃ (155.0mg, 474.0 μmol) in PhMe (10 mL) was stirred at 100° C. under N₂ for 12hours. The reaction mixture was concentrated in vacuo. The residue waspurified by silica gel column (EtOAc in Petroleum ether=30˜60%) to givetert-butylN-{1′-[3-(4-acetyl-1,2,3,4-tetrahydroquinoxalin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(130.0 mg, 81.2% yield) as a yellow solid.

Step b:

A solution of tert-butylN-{1′-[3-(4-acetyl-1,2,3,4-tetrahydroquinoxalin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(120.0 mg, 176.0 μmol) in TFA (1 mL) and DCM (5 mL) was stirred at 20°C. under N₂ for 12 hours. The reaction mixture was then poured intosaturated NaHCO₃ (50 mL), and extracted with DCM (30 mL×2). The organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel column (MeOH in DCM=0˜10%)to give1-[4-(6-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]ethan-1-one(85.0 mg, 91% purity, 89% yield) as a yellow solid. LCMS m/z[M+H]⁺=495.2.

Step c:

1-[4-(6-{3-Amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]ethan-1-one(85.0 mg, 171.0 μmol) was separated by preparative SFC (Column: DAICELCHIRALPAK AS-H (250 mm*30 mm, 5 um), Mobile phase: A: CO₂, B: Ethanol(0.1% NH₃.H₂O), Gradient: keep 50% of B, Flow rate: 50 mL/min, Columntemp: 35° C.) to give1-(4-{6-[(3R)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinoxalin-1-yl)ethan-1-one(32.0 mg, the faster eluting isomer, 38% yield) as a yellow solid (LCMSm/z [M+H]⁺=495.0, ¹HNMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.35 (d, J=8.4Hz, 1H), 7.22-7.30 (m, 1H), 7.12-7.18 (m, 3H), 6.92-7.08 (m, 2H),6.73-6.83 (m, 1H), 4.18-4.28 (m, 2H), 4.10-4.17 (m, 2H), 3.90-4.07 (m,3H), 3.15-3.35 (m, 2H), 3.05 (d, J=7.2 Hz, 1H), 2.69 (d, J=7.2 Hz, 1H),2.24 (s, 3H), 1.70-1.90 (m, 2H), 1.53-1.60 (m, 1H), 1.30-1.40 (m, 1H),SFC ee: 100%) and1-(4-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinoxalin-1-yl)ethan-1-one(35.0 mg, the slower eluting isomer, 41% yield) as a yellow solid (LCMSm/z [M+H]⁺=495.0, ¹HNMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.35 (d, J=8.4Hz, 1H), 7.22-7.30 (m, 1H), 7.12-7.18 (m, 3H), 6.92-7.08 (m, 2H),6.73-6.83 (m, 1H), 4.18-4.28 (m, 2H), 4.10-4.17 (m, 2H), 3.90-4.07 (m,3H), 3.15-3.35 (m, 2H), 3.05 (d, J=7.2 Hz, 1H), 2.69 (d, J=7.2 Hz, 1H),2.24 (s, 3H), 1.70-1.90 (m, 2H), 1.53-1.60 (m, 1H), 1.30-1.40 (m, 1H);SFC ee: 98.5%).

Method 1 Table: Compounds Synthesized Via Method 1, with theCross-Coupling of Various Amines and Iodides in Step a

LCMS Example Step a Step a m/z #^(a) Amine Iodide (M + H)⁺ ¹H NMR (400MHz, DMSO-d6) δ 3 W F 519.2 12.52-13.27 (m, 2H), 8.33 (s, 1H), 7.40-7.80(m, 3H), 7.28-7.38 (m, 1H), 7.10-7.23 (m, 3H), 6.66 (s, 1H), 4.21- 4.41(m, 2H), 3.94-4.04 (m, 2H), 3.88 (s, 1H), 3.18-3.27 (m, 2H), 3.10 (d, J= 15.6 Hz, 1H), 2.94-3.03 (m, 2H), 2.68 (d, J = 15.6 Hz, 1H), 2.05-2.16(m, 2H), 1.75-1.87 (m, 1H), 1.62-1.75 (m, 1H), 1.48-1.59 (m, 1H),1.10-1.21 (m, 1H). 4 W F 519.1 8.37 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H),7.96 (d, J = 9.2 Hz, 1H), 7.89 (s, 1H), 7.55-7.53 (m, 1H), 7.44-7.42 (m,3H), 7.03 (s, 1H), 4.57-4.54(m, 1H), 4.44- 4.41 (m, 2H), 4.12-4.11 (m,2H), 3.44- 3.42 (m, 2H), 3.39-3.38 (m, 2H), 3.33- 3.32 (m, 2H),2.34-2.32 (m, 2H), 1.96- 1.93 (m, 1H), 1.84-1.81 (m, 2H), 1.71- 1.68 (m,1H). 5 X F 533.1 8.12 (m, 1H), 7.90 (m,1H), 7.79 (m, 1H), 7.32-7.29 (m,1H), 7.27-7.24 (m, 1H), 7.18-7.11 (m, 4H), 4.34-4.27 (m, 2H), 3.98 (s,1H), 3.88-3.84 (m, 2H), 3.82 (s, 3H), 3.29-3.26 (m, 2H), 3.10- 3.06 (m,1H), 2.98-2.94 (m, 2H), 2.85- 2.80 (m, 1H), 2.13-2.06 (m, 2H), 1.80-1.68 (m, 2H), 1.55-1.42 (m, 2H). 6 X F 533.2 8.12 (m, 1H), 7.90 (m,1H),7.79 (m, 1H), 7.32-7.29 (m, 1H), 7.27-7.24 (m, 1H), 7.18-7.11 (m, 4H),4.34-4.27 (m, 2H), 3.98 (s, 1H), 3.88-3.84 (m, 2H), 3.82 (s, 3H),3.29-3.26 (m, 2H), 3.10- 3.06 (m, 1H), 2.98-2.94 (m, 2H), 2.85- 2.80 (m,1H), 2.13-2.06 (m, 2H), 1.80- 1.68 (m, 2H), 1.55-1.42 (m, 2H). 71,2,3,4- BB 417.2 tetrahydro- 1,5- naphthyridine (CAS# 13993-61-8)^(a)Step a was run anywhere from 80-100° C., for 2-12 h. NaOtBu couldalso be used as the base. Step b was run for 2-12 h; HCl/MeOH could alsobe used for the deprotection.

Compounds Synthesized in Similar Fashion to Method 1 Examples 8, 9, 10 &11: Synthesis of(1S,2S,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine,(1S,2R,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine,(1R,2R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine,and((1R,2S,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine

Step a:

1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine(40.0 mg, 96.0 μmol, Example 7) was separated by preparative SFC.Column: DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 um). Condition: 0.1%NH₃.H₂O EtOH. Begin B 30%, end B 30%. Flow rate: 50 mL/min.(1S,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine(16.0 mg, 96 umol, 40% yield) was obtained as a yellow solid and(1R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine(16.0 mg, 96 umol, 40% yield) was obtained as a yellow solid. Absolutestereochemistry of the diastereomers was arbitrarily assigned.

Step b:

A solution of(1S,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine(16.0 mg, 38.4 μmol), (Boc)₂O (8.4 mg, 38.4 μmol) and TEA (10.6 μL, 76.8μmol) in DCM (1.0 mL) was stirred at 15° C. for 15 mins. The reactionmixture was concentrated under reduced pressure. The residue waspurified by TLC (Ethyl acetate, 1% NH₃.H₂O). tert-butyl((1S,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(18.0 mg, 34.8 μmol, 91% yield) was obtained as a yellow solid. LCMS m/z[M+H]⁺=517.2.

Step c:

tert-butyl((1S,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(18 mg, 34.8 μmol) was separated by preparative SFC. Column: DAICELCHIRALPAK AD-H (250 mm×30 mm, 5 um). Condition: 0.1% NH₃.H₂O EtOH. BeginB 40%, end B 40%. Flow rate: 70 mL/min. tert-butyl((1S,2S,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(5.00 mg, 9.67 μmol, 100% ee, R_(t)=2.584 min) was obtained as a yellowsolid and tert-butyl((1S,2R,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(10.0 mg, 19.3 μmol, 100% ee, R_(t)=3.266 min) was obtained as a yellowsolid. Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂B: 40% of ethanol (0.05% DEA) Flow rate: 2.8 mL/min Column temperature:40° C.

Step d:

A solution of((1S,2S,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(5.0 mg, 9.7 μmol) in HCl/MeOH (2.0 mL, 4N) was stirred at 15° C. for0.5 hours. The reaction mixture was concentrated under reduced pressureto give the product(1S,4S,5S)-1′-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-4-aminehydrochloride (4.3 mg, 9.5 μmol, 95% yield) as a yellow solid. LCMS m/z[M+H]⁺=417.2. ¹HNMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 8.03-8.06 (m, 2H),7.55-7.58 (m, 1H), 4.51-4.56 (m, 1H), 4.36-4.40 (m, 1H), 4.07-4.10 (m,2H), 3.26-3.30 (m, 3H), 3.15-3.24 (m, 2H), 2.26-2.34 (m, 2H), 2.17-2.22(m, 1H), 1.94-1.97 (m, 1H), 1.62-1.80 (m, 5H), 1.47-1.52 (m, 1H),0.88-0.94 (m, 1H), 0.59-0.63 (m, 1H).

Step e:

A solution of tert-butyl((1S,2R,5S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(10.0 mg, 19.3 μmol) in HCl/MeOH (2 mL, 4N) was stirred at 15° C. for0.5 hours. The reaction mixture was concentrated under reduced pressureto give the product(1S,4R,5S)-1′-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-4-amine(7.2 mg, 17.2 μmol, 76.2% yield) as a yellow solid. LCMS m/z[M+H]⁺=417.2. ¹HNMR (400 MHz, CDCl₃): δ 8.32 (s, 1H), 8.03-8.06 (m, 2H),7.55-7.59 (m, 1H), 4.45-4.53 (m, 2H), 4.07-4.10 (m, 2H), 3.65-6.67 (m,1H), 3.27-3.30 (m, 2H), 3.14-3.21 (m, 2H), 2.28-2.34 (m, 2H), 2.16-2.22(m, 1H), 2.01-2.05 (m, 1H), 1.79-1.88 (m, 2H), 1.69-1.73 (m, 2H),1.54-1.64 (m, 2H), 0.80-0.85 (m, 1H), 0.68-0.73 (m, 1H).

Step f:

A solution(1R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine(16.0 mg, 38.4 μmol), (Boc)₂O (8.8 μL, 38.4 μmol) and TEA (10.6 uL, 76.8μmol) in DCM (2.0 mL) was stirred at 10° C. for 1 hour. The reactionmixture was concentrated under reduced pressure. The residue waspurified by TLC (Ethyl acetate, 1% NH₃.H₂O) to give tert-butyl((1R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(18.0 mg, 34.8 μmol, 90.9% yield) as a yellow solid. LCMS m/z[M+H]⁺=517.3.

Step g:

tert-butyl((1R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(18.0 mg, 34.8 μmol) was separated by preparative SFC. Column:Phenomenex-Cellulose-2 (250 mm×30 mm, 5 um). Condition: 0.1% NH₃.H₂OEtOH. Begin B 40%, end B 40%. Flow rate: 60 mL/min. tert-butyl((1R,2R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(6.0 mg, 11.6 μmol, 34% yield, SFC e.e. =100.0%, R_(t)=3.660 min) wasobtained as a yellow solid and tert-butyl((1R,2S,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(11.0 mg, 21.2 μmol, 61% yield, SFC e.e. =97.3%, R_(t)=4.290 min) wasobtained as a yellow solid. Column: Lux Cellulose-2 150×4.6 mm I.D., 3um Mobile phase: A: CO₂ B: 40% of ethanol (0.05% DEA) Flow rate: 2.8mL/min Column temperature: 40° C.

Step h:

A solution of tert-butyl((1R,2R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(6.0 mg, 11.6 μmol) in HCl/MeOH (2.0 mL, 4N) was stirred at 10° C. for 1hour. The reaction mixture was concentrated under reduced pressure togive the product(1R,2R,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine(5.0 mg, 10.2 umol, 88% yield, 2 HCl salt). LCMS m/z [M+H]⁺=417.1; ¹HNMR(400 MHz, CDCl₃): δ 8.32 (s, 1H), 8.04-8.07 (m, 2H), 7.56-7.59 (m, 1H),4.52-4.55 (m, 1H), 4.37-4.40 (m, 1H), 4.07-4.10 (m, 2H), 3.26-3.30 (m,3H), 3.18-3.24 (m, 2H), 2.29-2.34 (m, 2H), 2.18-2.21 (m, 1H), 1.94-1.97(m, 1H), 1.62-1.80 (m, 5H), 1.48-1.52 (m, 1H), 0.89-0.94 (m, 1H),0.60-0.63 (m, 1H).

Step i:

A solution of tert-butyl((1R,2S,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-yl)carbamate(11.0 mg, 21.2 μmol) in HCl/MeOH (2.0 mL, 4N) was stirred at 10° C. for1 hour. The reaction mixture was concentrated under reduced pressure togive the product(1R,2S,5R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)spiro[bicyclo[3.1.0]hexane-3,4′-piperidin]-2-amine(9.3 mg, 19.0 umol, 90% yield, 2 HCl salt). LCMS m/z [M+H]⁺=417.1; ¹HNMR(400 MHz, CDCl₃): δ 8.33 (s, 1H), 8.04-8.07 (m, 2H), 7.56-7.59 (m, 1H),4.45-4.53 (m, 2H), 4.07-4.10 (m, 2H), 3.66-6.67 (m, 1H), 3.28-3.30 (m,2H), 3.14-3.21 (m, 2H), 2.28-2.34 (m, 2H), 2.16-2.22 (m, 1H), 2.01-2.05(m, 1H), 1.80-1.89 (m, 2H), 1.69-1.73 (m, 2H), 1.55-1.66 (m, 2H),0.81-0.86 (m, 1H), 0.70-0.73 (m, 1H).

Method 2, Example 12: Synthesis of1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

1-(Oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl4-methylbenzene-1-sulfonate (531 mg, 1.05 mmol, Intermediate M) and1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine (214 mg, 1.05 mmol,Intermediate E) were taken up in DMF (25 mL). Diisopropylethylamine (916μL, 5.25 mmol) was added and the reaction mixture heated at 110° C. for16 hours. After cooling, the mixture was purified by reversed phase HPLC(0-30% acetonitrile/aq. HCl) to provide1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(12.0 mg, 21% yield) after lyophilization. LCMS m/z [M]⁺=537.6.

Step b:

1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminewas taken up in 4M HCl/dioxane (200 μL) and heated at 60° C. for 2 hrs.After cooling, the mixture was purified by reversed phase HPLC (5-10%acetonitrile/aq. HCl) to provide1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1i-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(6.0 mg, 60% yield). LCMS m/z (M+H)⁺=453.2; ¹H-NMR (400 MHz, DMSO-d₆) δ12.57 (br s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.89 (dd, J=1.22, 4.64 Hz,1H), 7.48 (dd, J=1.22, 8.30 Hz, 1H), 7.27-7.35 (m, 1H), 7.15-7.21 (m,1H), 6.95 (dd, J=4.52, 8.42 Hz, 1H), 4.31 (br dd, J=7.20, 12.08 Hz, 2H),3.93-3.99 (m, 2H), 3.90 (s, 1H), 3.17-3.31 (m, 4H), 3.10 (br d, J=15.87Hz, 1H), 2.93 (br t, J=6.47 Hz, 2H), 2.69 (br d, J=15.87 Hz, 1H), 2.06(td, J=6.20, 11.78 Hz, 2H), 1.65-1.85 (m, 2H), 1.53 (br d, J=12.94 Hz,1H), 1.17 (br d, J=13.43 Hz, 1H).

Method 2 Table: Compounds Synthesized Via Method 1, with theCross-Coupling of Various Amines and Tosylates in Step a

LCMS Example Step a Step a m/z #^(a) Amine Tosylate (M + H)⁺ ¹H NMR (400MHz, DMSO-d6) δ 13 N M 453.5 12.84 (s, 1H), 8.42 (s, 1H), 8.08 (br d, J= 4.88 Hz, 1H), 7.95 (br s, 3H), 7.32-7.42 (m, 2H), 7.22-7.30 (m, 2H),6.35-6.66 (m, 2H), 4.18-4.28 (m, 2H), 4.14 (br s, 1H), 3.95-4.06 (m,2H), 3.58 (br t, J = 10.99 Hz, 2H), 3.40-3.49 (m, 1H), 3.11 (br t, J =6.23 Hz, 2H), 2.92 (br d, J = 17.09 Hz, 1H), 2.53 (s, 2H), 2.04-2.21 (m,3H), 1.71-1.94 (m, 2H), 1.47-1.56 (m, 1H) 14^(b) N M 453.2 8.23 (s, 1H),7.88 (d, J = 20 Hz, 1H), 7.69 (d, J = 10 Hz, 1H), 7.31-7.19 (m, 5H),4.40-4.28 (m, 1H), 4.26- 4.15 (m, 1H), 4.12 (d, J = 4.8 Hz, 1H),3.95-3.93 (m, 2H), 3.59-3.46 (m, 3H), 3.10-3.07 (m, 2H), 2.91 (d, J =17.2 Hz, 1H), 2.25-2.14 (m, 3H), 1.94-1.78 (m, 2H), 1.67-1.60 (m, 1H)15^(b) N M 453.2 8.16 (s, 1H), 7.77-7.76 (m, 1H), 7.25-7.23 (m, 2H),7.19-7.17 (m, 1H), 7.12-7.10 (m, 2H), 6.92-6.89 (m, 1H), 4.23-4.14 (m,2H), 3.86-3.84 (m, 2H), 3.69-3.56 (m, 2H), 3.34-3.23 (m, 2H), 2.96-2.93(m, 2H), 2.69 (d, J = 17.6 Hz, 1H), 2.13-2.07 (m, 2H), 2.01-1.89 (m,2H), 1.80-1.70 (m, 1H), 1.63-1.57 (m, 1H) 16 V M 471.2 12.58 (br s, 1H),8.32 (s, 1H), 8.23 (s, 2H), 7.89 (d, J = 3.66 Hz, 1H), 7.48 (d, J = 8.30Hz, 1H), 7.21-7.28 (m, 1H), 7.16-7.21 (m, 1H), 7.01 (br t, J = 8.54 Hz,1H), 6.95 (dd, J = 4.39, 8.30 Hz, 1H), 4.31 (br d, J = 13.43 Hz, 2H),3.95 (br dd, J = 5.49, 10.86 Hz, 3H), 3.28 (q, J = 11.07 Hz, 2H), 3.15(br d, J = 16.11 Hz, 1H), 2.93 (br t, J = 6.47 Hz, 2H), 2.72 (br d, J =15.87 Hz, 1H), 2.01-2.10 (m, 2H), 1.66-1.84 (m, 2H), 1.55 (br d, J =12.94 Hz, 1H), 1.21 (br d, J = 12.70 Hz, 1H) 17 AD M 471.2 12.57 (br s,1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.89 (dd, J = 1.22, 4.39 Hz, 1H), 7.48(dd, J = 1.22, 8.30 Hz, 1H), 7.33 (dd, J = 5.62, 8.06 Hz, 1H), 6.87-7.08(m, 3H), 4.30 (br d, J = 13.43 Hz, 2H), 3.85-3.98 (m, 3H), 3.24 (q, J =11.56 Hz, 3H), 3.10 (br d, J = 16.11 Hz, 1H), 2.93 (t, J = 6.59 Hz, 2H),2.71 (br d, J = 16.11 Hz, 1H), 2.01-2.10 (m, 2H), 1.64-1.82 (m, 2H),1.52 (br d, J = 13.18 Hz, 1H), 1.21 (br d, J = 13.67 Hz, 1H) 18 AR M471.3 12.58 (br s, 1H), 8.32 (s, 1H), 8.18 (s, 2H), 7.89 (d, J = 4.15Hz, 1H), 7.48 (d, J = 8.56 Hz, 1H), 7.23-7.32 (m, 1H), 7.08 (d, J = 7.26Hz, 1H), 6.89-7.04 (m, 2H), 4.23 (s, 1H), 4.03-4.19 (m, 2H), 3.89-3.97(m, 2H), 3.38-3.51 (m, 2H), 3.15 (s, 1H), 3.08 (br d, J = 16.08 Hz, 1H),2.93 (br t, J = 6.35 Hz, 2H), 2.86 (br d, J = 16.08 Hz, 1H), 1.99-2.14(m, 2H), 1.78-1.91 (m, 1H), 1.53-1.63 (m, 2H), 1.42 (br d, J = 13.48 Hz,1H) ^(a)Step a was run anywhere from 100-110° C. for 3-16 h. Step b wasrun anywhere from 60-80° C. for 1-3 h. ^(b)Compound was separated viaSFC after Step b. Conditions: Column: DAICEL CHIRALPAK. IC (250 mm*30mm, 10 um); Mobile phase: 0.1% NH₃•H₂O, EtOH. Begin B: 55%. End B: 55%.Flow rate: 70 mL/min). Absolute stereochemistry of the enantiomers wasarbitrarily assigned.

Compounds Synthesized in Similar Fashion to Method 2 Examples 19 & 20:Synthesis of(R)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanoland(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol

Step a:

A solution of ethyl6-(2,3-dichlorophenyl)-5-methyl-3-[(4-methylbenzenesulfonyl)oxy]pyrazine-2-carboxylate(240.0 mg, 498.0 μmol, Intermediate AB) and1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine dihydrochloride (164.0mg, 597.0 μmol, Intermediate E) in DIPEA and NMP (4.0 mL/2.0 mL) wasstirred at 90° C. for 12 hours. The solution was poured into H₂O (20.0mL) and extracted with EtOAc (20.0 mL×2). The combined organic layerswere washed with brine (20.0 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by flash silica gel chromatography (12 g, ethyl acetate inpetroleum ether from 0% to 75%) to give ethyl3-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate(350.0 mg, quant. crude yield) as an orange oil. LCMS m/z(M+H)⁺=511.1/513.1.

Step b:

To a solution of ethyl3-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate(300.0 mg, 586.0 μmol) in CH₂Cl₂ (5.0 mL) was added DIBAL-H (878.0 uL,878.0 umol, 1M) at 0° C. under N₂. The mixture was stirred at 20° C. for1 hour. To the mixture was added 10% AcOH (30.0 mL) at 0° C. The mixturewas then extracted with CH₂Cl₂ (20.0 mL×2), and the combined organiclayers were washed with saturated NaHCO₃ (30.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (HCl) to afford(3-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanolhydrochloride (40.0 mg, 14% yield) as a yellow solid.

Step c:

(3-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanolhydrochloride (40.0 mg, 79.0 mmol) was separated by preparative SFC(column: DAICEL CHIRALPAK AS-H (250 mm×30 mm, 5 um), Mobile phase: 0.1%NH₃.H₂O MeOH (Begin B: 40%, End B: 40%), Flow rate: 55 mL/min) to affordthe product of(R)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol(7.70 mg, 20.8% yield, R_(t)=3.18 min, the faster eluting isomer) as awhite solid and(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol(8.50 mg, 22.9% yield, R_(t)=3.41 min, the slower eluting isomer) as awhite solid. Absolute stereochemistry of the enantiomers was arbitrarilyassigned. Characterization of(R)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol:LCMS m/z (M+H)⁺=469.1; ¹HNMR (400 MHz, CD₃OD): 7.52-7.55 (m, 1H),7.24-7.32 (m, 3H), 7.09-7.13 (m, 3H), 4.59 (s, 2H), 3.91 (s, 1H),3.57-3.61 (m, 2H), 3.01-3.14 (m, 3H), 2.68-2.73 (m, 1H), 2.16 (s, 3H),1.83-1.94 (m, 2H), 1.51-1.55 (m, 1H), 1.37-1.41 (m, 1H). SFC: e.e.=96.2%. Characterization of(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol:LCMS m/z (M+H)⁺=469.1; ¹HNMR (400 MHz, CD₃OD): 7.64-7.66 (m, 1H),7.38-7.44 (m, 3H), 7.22-7.25 (m, 3H), 4.71 (s, 2H), 4.03 (s, 1H),3.69-3.73 (m, 2H), 3.13-3.26 (m, 3H), 2.80-2.85 (m, 1H), 2.28 (s, 3H),1.93-2.07 (m, 2H), 1.63-1.67 (m, 1H), 1.49-1.53 (m, 1H). SFC: e.e.=97.3%, Column: Chiralpak AS-3 100×4.6 mm I.D., 3 m Mobile phase: A: CO₂B: Methanol (0.1% ethanolamine), Gradient: from 5% to 40% of B in 4.5min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8mL/min, Column temperature: 40° C.

Method 3, Examples 21 & 22: Synthesis of(3R)-1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amineand(3S)-1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

The mixture of 6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine (150 mg,546 μmol, 1.0 eq, Intermediate S),1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride (165 mg,600 μmol, 1.1 eq, Intermediate E) and Cs₂CO₃ (886 mg, 2.72 mmol, 5.0 eq)in NMP (1 mL) was stirred at 140° C. for 2 h under N₂ atmosphere. Themixture was diluted with saturated NaHCO₃ (20 mL), then extracted withEtOAc (20 mL×2). The organic layer was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by column chromatography (DCM/MeOH=1:0˜20:1) toafford1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(150 mg, 63% yield) as a yellow oil. LCMS m/z [M+H]⁺=440.1.

Step b:

The residue of1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(150 mg, 340 μmol, 1.0 eq) was separated by SFC (Column: DAICELCHIRALPAK AD (250 mm*30 mm, 10 um). Condition: 0.1% NH₃.H₂O EtOH. BeginB: 50%. End B: 50%. Flow rate: 70 mL/min.) to afford(3R)-1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(31.7 mg, 21% yield, the faster eluting isomer) as a yellow solid and(3S)-1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(42.6 mg, 29% yield, the slower eluting isomer) was obtained as a yellowsolid. Absolute stereochemistry of the enantiomers was arbitrarilyassigned. Characterization data for(3R)-1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine:LCMS m/z (M+H)⁺=439.9; ¹HNMR (400 MHz, Methanol-d₄): δ 7.63-7.59 (m,1H), 7.48 (s, 1H), 7.41-7.33 (m, 3H), 7.25-7.21 (m, 3H), 4.26-4.22 (m,2H), 3.99 (s, 1H), 3.25-3.15 (m, 3H), 2.86-2.81 (m, 1H), 1.92-1.76 (m,2H), 1.62-1.58 (m, 1H), 1.48-1.43 (m, 1H). SFC: e.e. =90.6%, R_(t)=5.279min. Column: Chiralpak AD-3 100×4.6 mm I.D., 3 m Mobile phase: 40% ofethanol (0.1% ethanolamine) in CO₂. Flow rate: 2.8 mL/min. Columntemperature: 40° C. for(3S)-1′-[6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine:LCMS m/z (M+H)⁺=439.9; ¹HNMR (400 MHz, Methanol-d₄): δ 7.63-7.60 (m,1H), 7.48 (s, 1H), 7.43-7.33 (m, 3H), 7.26-7.21 (m, 3H), 4.26-4.22 (m,2H), 3.99 (s, 1H), 3.25-3.15 (m, 3H), 2.86-2.81 (m, 1H), 1.92-1.76 (m,2H), 1.62-1.58 (m, 1H), 1.48-1.43 (m, 1H). SFC: e.e. =84.2%, R_(t)=7.362min. Column: Chiralpak AD-3 100×4.6 mm I.D., 3 m Mobile phase: 40% ofethanol (0.1% ethanolamine) in CO₂. Flow rate: 2.8 mL/min. Columntemperature: 40° C.

Method 3 Table: Compounds Synthesized Via Method 3, with the Coupling ofVarious Amines and Chlorides in Step a

Example Step a Step a LCMS m/z #^(e) Amine Chloride (M + H)⁺ ¹H NMR (400MHz, CD3OD) δ ppm 23^(a) T 6-chloro- 339.0 (DMSO) 13.06 (br s, 1H), 8.41(s, 1H- 1H), 8.01 (s, 1H), 7.19-7.25 (m, pyrazolo[3,4- 1H), 7.12-7.16(m, 1H), 6.96 (br t, b]pyrazine J = 8.67 Hz, 1H), 6.68 (br s, 1H),(synthesized 4.30 (br t, J = 12.21 Hz, 2H), 3.85 via Steps a-d (s, 1H),3.21-3.28 (m, 2H), 3.13 of (br d, J = 15.87 Hz, 1H), 2.63 (br d,Intermediate J = 15.87 Hz, 1H), 2.06 (s, 1H), A) 1.64-1.83 (m, 2H), 1.55(br d, J = 12.94Hz, 1H), 1.13 (br d, J = 13.43 Hz, 1H) 24^(a) V6-chloro- 339.0 (DMSO) 13.05 (br s, 1H), 8.41 (s, 1H- 1H), 8.01 (br s,1H), 7.18-7.26 (m, pyrazolo[3,4- 1H), 7.14 (d, J = 7.32 Hz, 1H), 6.97b]pyrazine (br t, J = 8.67 Hz, 1H), 6.51 (s, 1H), (synthesized 4.24-4.35(m, 2H), 3.86 (s, 1H), via Steps a-d 3.21-3.27 (m, 1H), 3.13 (br d, of J= 15.87 Hz, 1H), 2.63 (br d, Intermediate J = 15.87 Hz, 1H), 2.53 (s,1H), A) 1.78 (dt, J = 4.03, 12.51 Hz, 1H), 1.70 (dt, J = 4.03, 12.63 Hz,1H), 1.55 (br d, J = 13.18 Hz, 1H), 1.13 (br d, J = 13.92 Hz, 1H) 25^(b)E AA 453.2 8.28 (s, 1 H) 7.91 (d, J = 3.6 Hz, 1 H) 7.54-7.49 (m, 2 H)7.41-7.34 (m, 3 H) 7.13 (dd, J = 8.4, 4.8 Hz, 1 H) 4.52 (d, J = 13.6 Hz,1 H) 4.42- 4.38 (m, 2 H) 3.99-3.97 (m, 2 H) 3.44-3.40 (m, 2 H) 3.24-3.22(m, 2 H) 3.09 (t, J = 6.4 Hz, 2 H) 2.24-2.21 (m, 2 H) 1.93-1.64 (m, 4 H)26^(b) E AA 453.2 (CDCl3) 1.45 (d, J = 13.6 Hz, 1 H), 1.66 â€″ 1.93 (m,4 H) 2.21 (t, J = 5.6 Hz, 2 H) 2.78 (d, J = 15.6 Hz, 1 H) 3.08-3.16 (m,3 H) 3.32 â€″ 3.35 (m, 2 H) 4.03 (s, 1 H) 4.10 (t, J = 5.6 Hz, 2 H) 4.29â€″ 4.34 (m, 2 H) 6.96 â€″ 6.99 (m, 1 H) 7.25- 7.27 (m, 3 H) 7.36 (d, J= 4.4 Hz, 1 H) 7.66 (d, J = 7.6 Hz, 1 H) 8.06 â€″ 8.07 (m, 1 H) 8.16 (s,1 H) 9.94 (br s, 1 H) 27^(c) AI AA 524.2 8.26 (s, 1H), 7.87-7.89 (m,1H), 7.45 (s, 1H), 7.31-7.36 (m, 3H), 6.99-7.04 (m, 1H), 4.41-4.47 (m,2H), 4.01 (s, 1H), 3.94-3.97 (m, 2H), 3.35-3.39 28^(c) AI AA 524.2 8.26(s, 1H), 7.87-7.89 (m, 1H), 7.45 (s, 1H), 7.31-7.36 (m, 3H), 6.99-7.04(m, 1H), 4.41-4.47 (m, 2H), 4.01 (s, 1H), 3.94-3.97 (m, 2H), 3.35-3.3929^(d) AM AA 478.2 8.25 (s, 1H), 7.87-7.89 (m, 1H), 7.73 (s, 1H),7.56-7.61 (m, 1H), 7.42-7.47 (m, 1H), 7.32-7.36 (m, 1H), 7.00-7.03 (m,1H), 4.41-4.47 (m, 2H), 4.03 ^(a)Hunig's base was used as the amine andthe reaction was heated at 100° C. for 5 h. No Step b SFC was performedas amine was chiral. ^(b)In Step a, TEA was used as the base and themixture was heated at 85° C. for 12 h. Before chiral separation, the THPintermediate was deprotected using HCl/MeOH at rt for 0.5 h. ^(c)Theintermediate after Step A was protected with a BOC group beforepurification, then deprotected with HCl/MeOH before chiral separation.^(d)CsF was used as the base in Step a, and the reaction was run at 70°C. for 0.5 h. The intermediate of Step a was protected w ith a BOC groupbefore work up, then deprotected with HCl/MeOH before finalpurification. No Step b as the amine was chiral. ^(e)Absolutestereochemistry of the enantiomers was arbitrarily assigned.

Method 4, Example 30: Synthesis of(S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A round bottom flask was charged with tert-butyl((1S)-4-fluoro-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.3 g, 2.00 mmol, Intermediate U), 1,2,3,4-tetrahydro-1,5-naphthyridine(295 mg, 2.20 mmol),9-{[5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenyl-λ⁵-phosphanyl}-8-methyl-8-aza-9-palladatricyclo[8.4.0.0²,⁷]tetradeca-1(14),2(7),3,5,10,12-hexaen-9-ylmethanesulfonate (192 mg, 0.2 mmol), and (tert-butoxy)sodium (288 mg,3.00 mmol). The flask was evacuated and backfilled with N₂ three times.Then toluene (30 mL) was added and the reaction was stirred at 80° C.from 2 h. The reaction was then cooled to rt and diluted with EtOAc andpreabsorbed onto silica gel (5 g). The mixture was purified by columnchromatography (0-100% EtOAc in heptanes) to give tert-butyl((1S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.09 g, 83% yield). LCMS m/z (M+H)⁺=655.7.

Step b:

Dissolved t tert-butyl((1S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.09 g, 1.66 mmol) in MeOH (15 mL) and added hydrogen chloride (4.15mL, 16.6 mmol) and stirred at 60° C. for 2 h. The reaction wasconcentrated, then purified on by prep-HPLC (5-30% B, FA) to give(S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(465 mg, 60% yield). LCMS m/z (M+H)⁺=471.46; ¹H NMR (400 MHz, DMSO-d6)Shift 12.59 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.89 (dd, J=1.52, 4.55Hz, 1H), 7.49 (dd, J=1.39, 8.46 Hz, 1H), 7.22-7.35 (m, 2H), 7.09 (t,J=8.21 Hz, 1H), 6.96 (dd, J=4.55, 8.34 Hz, 1H), 4.33 (dt, J=4.29, 9.09Hz, 2H), 4.14 (s, 1H), 3.90-4.00 (m, 2H), 3.17 (br d, J=16.17 Hz, 1H),2.93 (t, J=6.44 Hz, 2H), 2.85 (br d, J=15.92 Hz, 1H), 2.53 (s, 1H),2.00-2.13 (m, 2H), 1.66-1.86 (m, 2H), 1.56 (br d, J=13.14 Hz, 1H), 1.34(br d, J=13.64 Hz, 1H).

Method 4 Table: Compounds Synthesized Via Method 4, with theCross-Coupling of Various Amines and Iodides in Step a

Example Step a Step a LCMS m/z #^(a) Amine Iodide (M + H)⁺ ¹H NMR (400MHz, DMSO-d6) δ ppm  31^(b) 5- F 530.1 12.64 (br s, 1H), 8.29 (s, 2H),7.34 (dd, methanesulfonyl- J = 0.98, 7.57 Hz, 1H), 7.28-7.32 (m,1,2,3,4- 1H), 7.10-7.22 (m, 5H), 4.22-4.37 (m, tetrahydroquinoline 2H),3.81-3.90 (m, 3H), 3.18-3.24 (m, (CAS# 7H), 3.09 (br d, J = 15.63 Hz,2H), 2.66 343944-90-1) (br d, J = 15.63 Hz, 1H), 2.02 (td, J = 6.23,11.96 Hz, 2H), 1.79 (dt, J = 3.91, 12.45 Hz, 1H), 1.68 (dt, J =3.66,12.45 Hz, 1H), 1.53 (br d, J = 12.94 Hz, 1H), 1.14 (br d, J = 13.18Hz, 1H)  32^(c) R F 562.2 8.27 (s, 1H), 7.29-7.37 (m, 1H), 7.14- 7.24(m, 3H), 6.84-6.92 (m, 2H), 6.82 (s, 1H), 4.28 (br d, J = 13.43 Hz, 2H),3.94-4.00 (m, 2H), 3.91 (br s, 1H), 3.69 (br dd, J = 7.20, 14.04 Hz,2H), 3.54-3.63 (m, 1H), 3.17-3.32 (m, 4H), 3.03-3.16 (m, 4H), 2.64-2.75(m, 3H), 1.81-1.92 (m, 2H), 1.70-1.80 (m, 1H), 1.60-1.69 (m, 1H), 1.51(br d, J = 12.94 Hz, 1H), 1.24 (br d, J = 12.21 Hz, 1H)  33^(c) Q F562.2 8.28-8.33 (m, 1H), 7.32-7.39 (m, 1H), 7.17-7.26 (m, 3H), 6.92 (s,2H), 6.70 (s, 1H), 4.31 (br d, J = 13.18 Hz, 2H), 4.11 (td, J = 7.20,14.40 Hz, 2H), 3.97-4.05 (m, 3H), 3.94 (ddd, J = 3.66, 6.35, 9.77 Hz,1H), 3.28-3.33 (m, 2H), 3.25 (br d, J = 9.28 Hz, 1H), 3.16-3.21 (m, 3H),3.11 (br d, J = 15.87 Hz, 1H), 3.00 (br d, J = 2.20 Hz, 1H), 2.77 (br d,J = 15.87 Hz, 1H), 2.26-2.40 (m, 4H), 1.76 (dt, J = 3.66, 12.45 Hz, 1H),1.62-1.71 (m, 1H), 1.52 (br d, J = 12.94 Hz, 1H), 1.27 (br d, J = 13.18Hz, 1H)  34^(c) O F 548.2 8.26 (br s, 1 H) 7.34 (br d, J = 6.74 Hz, 1 H)7.17-7.26 (m, 3 H) 6.85-6.89 (m, 1 H) 6.80-6.85 (m, 1 H) 6.78 (s, 1 H)4.28 (br d, J = 10.11 Hz, 2 H) 3.96 (br s, 5 H) 3.40-3.49 (m, 1 H)3.18-3.30 (m, 5 H) 3.09 (br d, J = 16.08 Hz, 1 H) 2.77 (br d, J = 16.08Hz, 1 H) 2.61-2.70 (m, 2 H) 1.81- 1.90 (m, 2 H) 1.69-1.77 (m, 1 H) 1.61-1.68 (m, 1 H) 1.50 (br d, J = 13.23 Hz, 1 H) 1.30 (br d, J = 11.41 Hz, 1H)  35^(b) P F 548.2 8.27-8.32 (m, 1H), 7.37 (br d, J = 5.86 Hz, 1H),7.18-7.28 (m, 3H), 6.86-6.94 (m, 2H), 6.67 (s, 1H), 4.31 (br dd, J =4.27, 9.40 Hz, 2H), 4.22 (ddd, J = 3.78, 7.02, 10.44 Hz, 1H), 4.11-4.18(m, 1H), 3.97-4.05 (m, 3H), 3.19-3.32 (m, 4H), 3.11 (br d, J = 15.87 Hz,1H), 2.80 (br d, J = 15.87 Hz, 1H), 2.29-2.39 (m, 2H), 2.18-2.27 (m,2H), 1.63-1.80 (m, 2H), 1.51 (br d, J = 12.45 Hz, 1H), 1.31 (br d, J =12.45 Hz, 1H)  36 1,2,3,4- Z 471.2 12.57 (br s, 1 H) 8.31 (s, 1 H) 8.20(s, 1 H) tetrahydro- 7.86-7.92 (m, 1 H) 7.48 (dd, J = 8.30, 1,5- 0.78Hz, 1 H) 7.21 (dd, J = 8.04, naphthyridine 5.45 Hz, 1 H) 7.09 (dd, J =8.82, 1.82 Hz, 1 H) 6.93-7.00 (m, 2 H) 4.31 (br t, J = 11.93 Hz, 2 H)3.91-3.97 (m, 2 H) 3.89 (s, 1 H) 3.23 (br dd, J = 21.65, 11.28 Hz, 2 H)3.08 (br d, J = 15.56 Hz, 1 H) 2.93 (t, J = 6.48 Hz, 2 H) 2.64 (br d, J= 15.30 Hz, 1 H) 2.06 (quin, J = 6.09 Hz, 2 H) 1.81 (td, 1 = 12.58,3.89Hz, 1 H) 1.67 (td, J = 12.58, 3.89 Hz, 1 H) 1.55 (br d, J = 12.97 Hz, 1H) 1.14 (br d, J = 12.97 Hz, 1 H  37 AE J 520.2 (CD3OD) 8.38 (s, 1H),8.23 (s, 1H), 8.02-8.10 (m, 2H), 7.53-7.55 (m, 2H), 7.41-7.46 (m, 2H),7.34-7.38 (m, 1H), 4.54-4.57 (m, 1H), 4.41-4.44 (m, 2H), 4.13-4.16 (m,2H), 3.44-3.52 (m, 2H), 3.38-3.42 (m, 2H), 3.24 (s, 2H), 2.32- 2.38 (m,2H), 1.91-1.99 (m, 1H), 1.81- 1.88 (m, 2H), 1.67-1.70 (m, 1H).  38 5- J530.5 12.64 (br s, 1H), 8.30 (s, 1H), 8.24 (s, methanesulfonyl- 1H),7.30-7.37 (m, 2H), 7.11-7.22 (m, 1,2,3,4- 5H), 4.30 (dt, J = 3.76, 8.36Hz, 2H), tetrahydroquinoline 3.91 (s, 1H), 3.86 (t, J = 5.83 Hz, 2H),(CAS# 3.25-3.30 (m, 3H), 3.21 (br d, J = 6.22 343944-90-1) Hz, 3H), 3.10(br d, J = 15.82 Hz, 1H), 2.69 (br d, J = 15.82 Hz, 1H), 2.02 (quin, J =6.09 Hz, 2H), 1.79 (dt, J = 4.15, 12.58 Hz, 1H), 1.69 (dt, J = 3.89,12.58 Hz, 1H), 1.53 (br d, J = 12.45 Hz, 1H), 1.17 (br d, J = 14.00 Hz,1H)  39 AF J 543.2 12.85 (br s, 1H), 8.35 (s, 1H), 8.25 (s, 1H),7.29-7.35 (m, 2H), 7.16-7.21 (m, 3H), 7.09-7.13 (m, 1H), 7.05-7.08 (m,1H), 4.26-4.36 (m, 2H), 4.04 (br t, J = 4.54 Hz, 2H), 3.89 (s, 1H), 3.27(br d, J = 11.15 Hz, 4H), 3.10 (br d, J = 15.56 Hz, 2H), 2.68 (d, J =15.82 Hz, 1H), 1.64-1.83 (m, 4H), 1.53 (br d, J = 12.71 Hz, 1H), 1.44(br d, J = 2.59 Hz, 2H), 1.17 (br d, J = 13.23 Hz, 1H)  40 X Z 551.212.51 (s, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.55 (d, J =8.56 Hz, 1H), 7.23 (d, J = 8.56 Hz, 1H), 7.19 (dd, J = 5.45, 7.78 Hz,1H), 7.06 (br d, J = 7.78 Hz, 1H), 6.91-6.97 (m, 1H), 4.25-4.36 (m, 2H),3.94-4.00 (m, 2H), 3.81-3.87 (m, 4H), 3.14-3.26 (m, 2H), 3.07 (br d, J =15.56 Hz, 1H), 2.93 (br t, J = 6.48 Hz, 2H), 2.59 (br d, J = 15.30 Hz,1H), 2.04- 2.08 (m, 2H), 1.81 (dt, J = 3.89, 12.58 Hz, 1H), 1.63-1.71(m, 1H), 1.55 (br d, J = 13.23 Hz, 1H), 1.09 (br d, J = 13.23 Hz, 1H) 41 5- Z 548.5 12.64 (br s, 1H), 8.29 (s, 1H), 8.23 (s, methanesulfonyl-1H), 7.34 (d, J = 7.52 Hz, 1H), 7.17-7.23 1,2,3,4- (m, 2H), 7.10-7.16(m, 1H), 7.08 (br d, tetrahydroquinoline J = 8.04 Hz, 1H), 6.91-6.99 (m,1H), 4.31 (CAS# (br t, J = 13.35 Hz, 2H), 3.83-3.89 (m, 343944-90-1)4H), 3.23 (s, 4H), 3.07 (br d, J = 15.56 Hz, 2H), 2.61 (br d, J = 15.30Hz, 1H), 2.02 (quin, J = 5.96 Hz, 2H), 1.80 (dt, J = 3.76, 12.51 Hz,1H), 1.61-1.71 (m, 1H), 1.55 (br d, J = 12.71 Hz, 1H), 1.11 (br d, J =13.23 Hz, 1H)  42 X U 551.2 12.51 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H),7.82 (d, J = 0.76 Hz, 1H), 7.55 (d, J = 8.59 Hz, 1H), 7.19-7.28 (m, 2H),7.13-7.18 (m, 1H), 6.98 (t, J = 8.59 Hz, 1H), 4.30 (dt, J = 3.79, 8.08Hz, 2H), 3.95-4.00 (m, 2H), 3.90 (s, 1H), 3.84 (s, 3H), 3.24 (br s, 1H),3.14 (d, J = 15.92 Hz, 1H), 2.93 (t, J = 6.44 Hz, 2H), 2.67 (br d, J =15.92 Hz, 1H), 2.02-2.12 (m, 2H), 1.65-1.84 (m, 3H), 1.55 (br d, J =12.13 Hz, 1H), 1.16 (br d, J = 13.14 Hz, 1H)  43 AO J 492.2 (CD3OD) 8.21(s, 1H), 7.35-7.34 (m, 1H), 7.21-7.17 (m, 3H), 6.85-6.80 (m, 3H), 4.37(d, J = 13.6 Hz, 2H), 3.45 (d, J = 4.8 Hz, 2H), 3.94 (s, 1H), 3.46-3.36(m, 4H), 3.16 (d, J = 15.6 Hz, 1H), 2.96 (s, 3H), 2.81 (d, J = 15.6 Hz,1H), 1.90- 1.76 (m, 2H), 1.61 (d, J = 14.0 Hz, 1H), 2.69 (d, J = 11.2Hz, 1H).  44 AQ J 483.4 12.78 (br s, 1H), 8.37 (s, 1H), 8.23 (s, 1H),7.30-7.37 (m, 1H), 7.14-7.25 (m, 4H), 5.86 (d, J = 7.83 Hz, 1H),4.26-4.37 (m, 2H), 3.92 (s, 1H), 3.71-3.80 (m, 2H), 3.30 (s, 3H), 3.26(br d, J = 13.89 Hz, 2H), 3.11 (d, J = 15.66 Hz, 1H), 2.65-2.76 (m, 1H),1.93 (quin, J = 5.87 Hz, 2H), 1.80 (dt, J = 4.04, 12.51 Hz, 1H), 1.69(dt, J = 3.66, 12.44 Hz, 1H), 1.53 (br d, J = 12.63 Hz, 1H), 1.18 (br d,J = 13.89 Hz, 1H)  45^(b) 1,2,3,4- AU 454.2 12.57 (s, 1H), 8.30-8.35 (m,2H), 7.89 tetrahydro- (d, J = 4.15 Hz, 1H), 7.60 (br d, J = 7.26 1,5-Hz, 1H), 7.48 (d, J = 8.30 Hz, 1H), 7.16 naphthyridine (dd, J = 4.93,7.26 Hz, 1H), 6.95 (dd, J = 4.41, 8.30 Hz, 1H), 4.22 (br t, J = 12.84Hz, 2H), 3.92-3.97 (m, 2H), 3.88 (s, 1H), 3.36 (br s, 2H), 3.08 (br d, J= 16.08 Hz, 1H), 2.93 (t, J = 6.35 Hz, 2H), 2.67 (br d, J = 16.08 Hz,1H), 2.03- 2.09 (m, 2H), 1.74-1.86 (m, 2H), 1.58 (br d, J = 13.23 Hz,1H), 1.15 (br d, J = 13.48 Hz, 1H)  46^(b) X AU 534.3 12.51 (s, 1H),8.33 (br d, J = 4.41 Hz, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H),7.60 (d, J = 7.52 Hz, 1H), 7.55 (d, J = 8.56 Hz, 1H), 7.23 (d, J = 8.82Hz, 1H), 7.16 (dd, J = 5.19, 7.26 Hz, 1H), 4.18-4.27 (m, 2H), 3.95-4.00(m, 2H), 3.88 (s, 1H), 3.84 (s, 3H), 3.36 (br s, 2H), 3.08 (br d, J =16.08 Hz, 1H), 2.93 (br t, J = 6.48 Hz, 2H), 2.67 (br d, J = 15.82 Hz,1H), 2.07 (quin, J = 5.83 Hz, 2H), 1.75-1.86 (m, 2H), 1.58 (br d, J =13.48 Hz, 1H), 1.15 (br d, J = 13.48 Hz, 1H)  47 1,2,3,4- AX 471.3 12.58(br s, 1H), 8.31 (s, 1H), 8.20 (s, tetrahydro- 2H), 7.89 (d, J = 4.15Hz, 1H), 7.48 (d, 1,5- J = 8.30 Hz, 1H), 7.22-7.29 (m, 1H), 7.07naphthyridine (d, J = 7.52 Hz, 1H), 6.93-7.01 (m, 2H), 4.10-4.20 (m,3H), 4.02-4.09 (m, 2H), 3.91-3.97 (m, 3H), 3.45 (dt, J = 10.89, 13.23Hz, 3H), 3.05 (br d, J = 16.08 Hz, 1H), 2.93 (t, J = 6.48 Hz, 2H), 2.82(br d, J = 16.08 Hz, 1H), 2.53 (s, 1H), 2.03-2.10 (m, 2H), 1.81-1.89 (m,1H), 1.51-1.61 (m, 2H), 1.41 (br d, J = 13.48 Hz, 1H)  48 X AX 551.312.51 (s, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.55 (d, J =8.56 Hz, 1H), 7.16-7.30 (m, 2H), 7.04 (d, J = 7.26 Hz, 1H), 6.94 (t, J =8.82 Hz, 1H), 3.95-4.12 (m, 5H), 3.84 (s, 3H), 3.44-3.55 (m, 2H), 3.01(br d, J = 16.08 Hz, 1H), 2.93 (br t, J = 6.35 Hz, 2H), 2.77 (br d, J =16.08 Hz, 1H), 2.03-2.10 (m, 2H), 1.82-1.91 (m, 1H), 1.48-1.58 (m, 2H),1.38-1.46 (m, 1H)  49 1,2,3,4- AZ 454.2 12.57 (s, 1H), 8.27-8.40 (m,2H), 7.87- tetrahydro- 7.92 (m, 1H), 7.64 (d, J = 7.26 Hz, 1H), 1,5-7.48 (d, J = 8.30 Hz, 1H), 7.16 (dd, naphthyridine J = 5.19, 7.26 Hz,1H), 6.95 (dd, J = 4.67, 8.30 Hz, 1H), 4.26-4.36 (m, 2H), 3.91- 3.97 (m,2H), 3.89 (s, 1H), 3.20-3.29 (m, 3H), 3.12 (d, J = 16.34 Hz, 1H), 2.93(t, J = 6.48 Hz, 2H), 2.76 (br d, J = 16.08 Hz, 1H), 2.01-2.10 (m, 3H),1.68-1.83 (m, 2H), 1.55 (br d, J = 12.97 Hz, 1H), 1.14 (br d, J = 12.97Hz, 1H)  50 1,2,3,4- BD 454.3 12.56 (s, 1H), 8.46 (s, 1H), 8.34 (d,tetrahydro- J = 4.67 Hz, 1H), 8.31 (s, 1H), 7.89 (d, 1,5- J = 4.41 Hz,1H), 7.48 (d, J = 8.30 Hz, naphthyridine 1H), 7.23 (d, J = 4.93 Hz, 1H),6.95 (dd, J = 4.67, 8.30 Hz, 1H), 4.27 (br t, J = 12.19 Hz, 2H),3.90-3.98 (m, 3H), 3.20-3.28 (m, 2H), 3.10 (d, J = 16.60 Hz, 1H), 2.93(t, J = 6.48 Hz, 2H), 2.68 (br d, J = 16.60 Hz, 1H), 2.03-2.09 (m, 2H),1.85 (br d, J = 6.22 Hz, 1H), 1.67-1.80 (m, 3H), 1.52 (br d, J = 13.48Hz, 1H), 1.14 (br d, J = 13.74 Hz, 1H)  51 BG J 521.4 12.72 (s, 1H),8.27 (br s, 3H), 7.51 (d, J = 7.26 Hz, 1H), 7.27-7.39 (m, 3H), 7.18 (d,J = 8.30 Hz, 1H), 6.97 (d, J = 8.56 Hz, 1H), 4.30-4.42 (m, 5H),3.85-3.95 (m, 2H), 3.20 (br d, J = 16.08 Hz, 1H), 2.99- 3.07 (m, 4H),2.77 (br t, J = 6.35 Hz, 2H), 1.99-2.10 (m, 2H), 1.70-1.83 (m, 2H), 1.53(br d, J = 12.97 Hz, 2H)  52 BW BY 501.5 12.78 (br s, 1H), 8.37 (s, 1H),8.21 (s, 1H), 7.33 (dd, J = 5.45, 8.04 Hz, 1H), 7.19 (d, J = 7.78 Hz,1H), 6.96-7.07 (m, 2H), 5.86 (d, J = 7.52 Hz, 1H), 4.30 (br dd, J =2.33, 12.97 Hz, 2H), 3.88 (s, 1H), 3.72-3.79 (m, 3H), 3.30 (s, 4H), 3.25(br d, J = 14.00 Hz, 3H), 3.10 (br d, J = 16.08 Hz, 1H), 2.71 (br d, J =16.08 Hz, 1H), 1.93 (quin, J = 5.90 Hz, 2H), 1.73-1.83 (m, 1H),1.63-1.72 (m, 1H), 1.53 (br d, J = 12.97 Hz, 1H)  53 BW U 501.5 12.78(br s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.22-7.31 (m, 1H), 7.15-7.21 (m,2H), 7.01 (t, J = 8.69 Hz, 1H), 5.86 (d, J = 7.78 Hz, 1H), 4.27-4.35 (m,2H), 3.97 (br s, 1H), 3.73-3.77 (m, 2H), 3.25-3.34 (m, 5H), 3.15 (d, J =15.82 Hz, 1H), 2.72 (br d, J = 15.82 Hz, 1H), 1.93 (quin, J = 5.90 Hz,2H), 1.75-1.84 (m, 1H), 1.66-1.74 (m, 1H), 1.56 (br d, J = 12.97 Hz,1H), 1.21 (br d, J = 12.97 Hz, 1H)  54 1,2,3,4- CA 473.5 12.65 (br s,1H), 8.38 (s, 1H), 8.13 (s, tetrahydro- 1H), 7.90 (dd, J = 1.17, 4.54Hz, 1H), 1,5- 7.45-7.52 (m, 1H), 7.22 (d, J = 7.26 Hz, naphthyridine1H), 7.14 (dd, J = 8.56, 10.63 Hz, 1H), 6.96 (dd, J = 4.54, 8.43 Hz,1H), 6.91 (dt, J = 4.28, 7.84 Hz, 1H), 4.41 (br d, J = 13.48 Hz, 1H),4.29-4.35 (m, 2H), 3.93-3.99 (m, 2H), 3.41-3.48 (m, 3H), 2.94 (t, J =6.48 Hz, 2H), 1.97-2.10 (m, 3H), 1.87-1.93 (m, 1H), 1.80-1.86 (m, 2H) 55 BW CA 503.5 12.83 (s, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.20 (d, J =7.78 Hz, 1H), 7.15 (d, J = 7.52 Hz, 1H), 7.07 (dd, J = 8.30, 10.89 Hz,1H), 6.86 (dt, J = 4.41, 7.78 Hz, 1H), 5.86 (d, J = 7.52 Hz, 1H), 4.36(br d, J = 13.23 Hz, 1H), 4.28 (br d, J = 13.74 Hz, 1H), 4.15 (s, 1H),3.72-3.78 (m, 3H), 3.43-3.53 (m, 3H), 3.30 (s, 3H), 1.90-2.01 (m, 4H),1.74-1.88 (m, 4H)  56 5- U 548.4 12.69 (s, 1H), 8.34 (s, 2H), 7.32-7.41methanesulfonyl- (m, 2H), 7.10-7.25 (m, 2H), 4.28-4.48 1,2,3,4- (m, 3H),3.84-3.90 (m, 1H), 3.27-3.37 tetrahydroquinoline (m, 2H), 3.15-3.26 (m,4H), 3.07 (br d, (CAS# J = 16.17 Hz, 1H), 2.02 (td, J = 6.19, 11.87343944-90-1) Hz, 2H), 1.69-1.86 (m, 3H), 1.49-1.61 (m, 2H), 0.99-1.28(m, 5H)  57 BW CC 485.5 12.83 (s, 1H), 8.43 (s, 1H), 7.35 (d, J = 7.33Hz, 1H), 7.12-7.24 (m, 2H), 6.89 (dt, J = 0.88, 7.39 Hz, 1H), 6.81 (d, J= 8.08 Hz, 1H), 5.86 (d, J = 7.83 Hz, 1H), 4.26-4.44 (m, 2H), 4.17 (s,1H), 3.68-3.80 (m, 2H), 3.39-3.53 (m, 2H), 3.30 (s, 4H), 1.88-2.04 (m,3H), 1.67- 1.88 (m, 4H)  58 BW Z 501.5 8.35 (s, 1 H), 8.26-8.30 (m, 1H), 7.23- 7.26 (m, 1 H), 7.20 (d, J = 7.78 Hz, 1 H), 7.14 (dd, J =8.95,1.94 Hz, 1 H), 6.93-7.06 (m, 1 H), 5.85 (d, J = 7.52 Hz, 1 H), 4.32(br d, J = 13.48 Hz, 2 H), 3.96 (s, 1 H), 3.67-3.77 (m, 2 H), 3.30- 3.33(m, 3 H), 3.16-3.29 (m, 2 H), 3.09 (d, J = 15.82 Hz, 1 H), 2.66-2.75 (m,1 H), 2.48 (br s, 2 H), 1.88-1.97 (m, 2 H), 1.74-1.84 (m, 1 H), 1.67(td, J = 12.45, 3.89 Hz, 1 H), 1.55 (br d, J = 12.97 Hz, 1 H), 1.16-1.30(m, 1 H).  59 5- AX 548.6 12.64 (br s, 1H), 8.29 (s, 1H), 8.18 (s,methanesulfonyl- 1H), 7.34 (dd, J = 1.26, 7.58 Hz, 1H), 1,2,3,4-7.17-7.26 (m, 2H), 7.10-7.16 (m, 1H), tetrahydroquinoline 7.04 (d, J =7.33 Hz, 1H), 6.95 (t, J = 8.97 (CAS# Hz, 1H), 3.99-4.13 (m, 3H),3.82-3.89 343944-90-1) (m, 2H), 3.43-3.53 (m, 2H), 3.19-3.24 (m, 5H),3.02 (d, J = 16.17 Hz, 1H), 2.78 (d, J = 16.17 Hz, 1H), 2.02 (quin, J =6.13 Hz, 2H), 1.81-1.90 (m, 1H), 1.49-1.59 (m, 2H), 1.41 (br d, J =13.64 Hz, 1H)  60 X CC 535.1 (CD3OD) 8.40-8.37 (m, 2H), 8.14-8.12 (m,2H), 7.77-7.75 (m, 1H), 7.59-7.58 (m, 1H), 7.46-7.42 (m, 1H), 7.11-7.01(m, 2H), 4.99-4.91 (m, 2H), 4.87-4.86 (m, 1H), 4.84-7.77 (m, 1H),4.70-4.68 (m, 1H), 4.13-4.11 (m, 2H), 4.02 (s, 3H), 3.58-3.32 (m, 2H),2.35-2.31 (m, 2H), 2.19-2.15 (m, 2H), 1.95-1.92 (m, 2H).  61 AE CC 522.112.95 (br, 1H), 8.79 (br, 3H), 8.45 (s, 1H), 8.19 (s, 1H), 7.75-7.73 (d,J = 8.8 Hz, 1H), 7.71-7.68 (d, J = 7.6 Hz, 1H), 7.63-7.60 (d, J = 8.8Hz, 1H), 7.39-7.34 (m, 2H), 7.04-6.97 (m, 2H), 4.66-4.43 (m, 3H),4.04-4.01 (m, 2H), 3.42-3.35 (m, 2H), 3.08-3.04 (m, 2H), 2.18-1.84 (m,6H).  62 1,2,3,4- CS 489.0 (CD3OD) 8.36 (s, 1H), 8.08-8.05 (m,tetrahydro- 2H), 7.61-7.55 (m, 1H), 7.26-7.15 (m, 1,5- 2H), 4.69 (s,1H), 4.56-4.40 (m, 2H), naphthyridine 4.12-4.09 (m, 2H), 3.53-3.45 (m,2H), 3.31-3.26 (m, 4H), 2.34-2.29 (m, 2H), 2.00-1.83 (m, 3H), 1.73-1.68(m, 1H).  63^(d) (R)-N- CJ 439.1 (CD3OD) 8.58 (s, 2H), 7.74-7.72 (d, J =[(3S)-1,3- 6.8 Hz, 1H), 7.55-7.36 (m, 4H), 6.95- dihydrospiro- 6.92 (d,J = 6.8 Hz, 1H), 4.45 (s, 1H), [indene-2,4′- 3.96-3.82 (m, 2H),3.29-3.19 (m, 4H), piperidin]- 2.04-1.68 (m, 4H). 3-yl]-2- methyl-propane-2- sulfinamide (synthesized via Step a of Example 120  64^(d) CBBS 444.0 (CD3OD) 8.19-8.20 (m, 1H), 8.12-8.13 (m, 1H), 8.00-8.01 (m,1H), 7.39-7.42 (m, 1H), 7.18-7.23 (m, 1H), 7.02-7.03 (m, 1H), 6.90-6.94(m, 1H), 6.80-6.82 (m, 1H), 4.33-4.37 (m, 1H), 4.23-4.26 (m, 1H), 4.13(s, 1H), 3.42-3.49 (m, 2H), 1.95-2.05 (m, 2H), 1.84-1.88 (m, 1H).176^(d) (2S)-2- CZ 440.1 (CD3OD) 5 8.15 (s, 1H), 7.86 (s, 1H),phenylpiperidine 7.50-7.40 (m, 1H), 7.38-7.30 (m, 8H), (CAS # 4.37 (s,1H), 4.29 (d, J = 14.0 Hz, 1H), 70665-05-3) 4.13 (d, J = 13.6 Hz, 1H),4.00-3.92 (m, 1H), 3.69-3.66 (m, 1H), 3.26-3.20 (m, 2H), 3.14 (s, 2H),2.36-2.08 (m, 5H), 1.95-1.60 (m, 6H). 196^(e) 1,2,3,4- DW 427.3(MeOD-d4) 8.19 (s, 1H), 8.19-8.15 (m, tetrahydro- 2H), 8.13 (d, J = 5.6Hz, 1H), 7.64-7.60 1,5- (m, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.42-naphthyridine 7.35 (m, 3H), 4.49 (s, 1H), 3.93-3.90 (m, 2H), 3.70-3.56(m, 2H), 3.56-3.37 (m, 2H), 3.25-3.19 (m, 4H), 2.59 (s, 3H), 2.28-2.25(m, 2H), 2.24- 2.05 (m, 2H), 1.89 (d, J = 13.2 Hz, 1H), 1.74 (d, J =13.6 Hz, 1H). 197^(d) 1,2,3,4- DV 427.3 (MeOD-d4) 8.19 (s, 1H), 7.98 (d,J = tetrahydro- 5.2 Hz, 1H), 7.55-7.52 (m, 2H), 7.42- 1,5- 7.37 (m, 2H),7.37-7.35 (m, 1H), 7.20 naphthyridine (d, J = 8.8 Hz, 1H), 4.44-4.42 (m,2H), 4.32-4.28 (m, 1H), 3.69-3.67 (m, 2H), 3.42-3.36 (m, 2H), 3.26-3.21(m, 4H), 2.35 (s, 3H), 2.31- 2.25 (m, 2H), 1.97-1.96 (m, 1H), 1.87- 1.78(m, 1H), 1.69 (d, J = 13.2 Hz, 1H). 198^(d,f) EF EE 438.3 8.96-8.95 (m,1H), 8.43-8.41 (m, 1H), 8.27 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.96 (d.J = 8.0 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H),7.64-7.59 (m, 2H), 7.38-7.36 (m, 1H), 7.24-7.19 (m, 3H), 5.94 (s, 2H),4.00- 3.99 (m, 3H), 3.08-2.98 (m, 3H), 2.71 (d, J = 16.0 Hz, 1H),1.84-1.67 (m, 2H), 1.49 (br d, J = 12.8 Hz, 1H), 1.23 (br d, J = 13.2Hz, 1H). 199 pyridin-3- EK 400.3 13.19 (br s, 1 H), 8.76 (br s, 2 H),8.63 ylmethanamine (br s, 1 H), 8.51 (br s, 1 H), 8.20 (br s, 1 (CAS#H), 7.82-7.78 (m, 2 H), 7.64 (br d, J = 3731-52-0) 7.6 Hz, 1 H), 7.42(br s, 1 H), 7.33- 7.29 (m, 3 H), 6.65 (br d, J = 7.2 Hz, 1 H), 4.66 (brd, J = 5.6 Hz, 2 H), 4.38 (br s, 1 H), 3.22-3.14 (m, 5 H), 2.95 (br d, J= 16.0 Hz, 1 H), 2.16 (s, 3 H), 2.06-1.90 (m, 2 H) 1.64-1.53 (m, 2 H)200^(g) piperidine DS 434.1 (MeOD-d4) 8.56 (s, 1H), 7.46 (d, J = 6.5 Hz,1H), 7.36-7.23 (m, 3H), 4.23 (s, 1H), 3.59-3.48 (m, 5H), 3.47-3.40 (m,4H), 3.21-3.11 (m, 3H), 2.97 (d, J = 16.1 Hz, 1H), 2.04-1.93 (m, 2H),1.78-1.59 (m, 8H) 201 EF EO 399.2 (MeOD-d4) 8.52 (s, 1 H), 8.13-8.10 (m,1 H), 7.86-7.85 (m, 1 H), 7.59- 7.57 (m, 1 H), 7.52-7.51 (m, 1 H),7.48-7.46 (d, J = 6.8 Hz, 1 H), 7.34- 7.28 (m, 4 H), 6.53 (d, J = 2.0 Hz1 H), 4.32-4.29 (m, 1 H), 3.81 (s, 3 H), 3.50-3.47 (m, 2 H), 3.15-3.11(m, 2 H), 3.05-3.0 (m, 2 H), 2.05-1.94 (m, 2 H), 1.75-1.67 (m, 2 H)202^(h) EF EP 385.0 (MeOD-d4) 8.40 (s, 2H), 7.91 (s, 1 H), 7.82 (s, 1H), 7.53 (s, 1 H), 7.51 (s, 1 H), 7.42-7.32 (m, 3 H), 7.39-7.02 (m, 1H), 7.05 (s, 1 H), 4.43 (s, 1 H), 3.54- 3.50 (d, J = 12.4 Hz, 1 H),3.46-3.54 (m, 2 H), 3.45-3.41 (d, J = 12.4 Hz, 2 H), 3.12 (s, 2 H),3.02-2.94 (m, 2 H), 2.06-2.01 (m, 1 H), 1.97-1.90 (m, 1 H), 1.83-1.80(d, J = 11.6 Hz, 1H), 1.70-1.66 (d, J = 12.8 Hz, 1H) 203^(e,j) EW EV477.1 (M − (CDCl3) 8.59 (d, J = 8.0 Hz, 1H), 8.31 NH₂)⁺ (s, 1H), 8.11(s, 1H), 7.86-7.84 (m, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.2Hz, 1H), 7.25-7.23 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.95 (t, J = 7.2Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 4.29 (s,1H), 3.63 (s, 3H), 3.56-3.47 (m, 2H), 3.45-3.41 (m, 2H), 2.67 (s, 3H),2.25-2.18 (m, 1H), 2.08 (s, 1H), 1.97 (t, J = 5.8 Hz, 1H). 204piperidine FW 397.1 (MeOD-d4) 7.54~7.56 (m, 1H), 7.32~7.43 (m, 4H),4.91~4.93 (m, 4H), 4.48 (s, 1H), 3.50~3.73 (m, 4H), 3.15~3.28 (m, 2H),1.61~1.97 (m, 10H). 205^(k) 1,2,3,4- DQ 442.1 (MeOD-d4) 7.83 (s, 1H),7.51 (m, 1H), tetrahydroquinolin 7.42-7.17 (m, 4H), 7.06-6.76 (m, 2H),6.61 (m, 1H), 6.29 (m, 1H), 4.37 (s, 1H), 3.57 (s, 3H), 3.55-3.44 (m,4H), 3.24-3.06 (m, 4H), 2.86 (m, 2H), 2.13- 1.91 (m, 4H), 1.79-1.64 (m,2H) 206^(k) EF FG 441.1 8.60 (s, 3H), 7.60 (d, J = 7.2 Hz, 1H),7.38-7.30 (m, 4H), 6.90 (d, J = 7.6 Hz, 1H), 6.81-6.77 (m, 1H), 6.49 (t,J = 7.2 Hz, 1H), 6.12 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 7.6 Hz, 1H),4.40 (d, J = 4.4 Hz, 1H), 3.47 (s, 3H), 3.41-3.38 (m, 2H), 3.18-2.93 (m,4H), 2.84-2.73 (m, 4H), 1.97-1.91 (m, 4H\ 1.62-1.54 (m, 2H). 207^(l)1,2,3,4- FH 471.1 (MeOD-d4) 7.55 (d, J = 7.6 Hz, 1H), tetrahydroquinolin7.47-7.36 (m, 3H), 7.08 (d, J = 7.2 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H),6.76 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 4.49 (s, 1H),4.08-4.00 (m, 1H), 3.93- 3.85 (m, 1H), 3.66-3.55 (m, 4H), 3.23 (s, 2H),2.92 (t, J = 6.4 Hz, 1H), 2.33 (s, 3H), 2.16-1.92 (m, 4H), 1.90-1.82 (m,1H), 1.77-1.69 (m, 1H). 208 piperidine FL 438.1 (MeOD-d4) 7.38-7.35 (m,1H), 7.21- 7.16 (m, 1H), 7.02-6.99 (m, 1H), 4.75 (s, 1H), 4.21-4.14 (m,1H), 4.14-3.91 (m, 5H), 3.55-3.42 (m, 2H), 2.68 (s, 3H), 2.39-2.31 (m,1H), 2.18-1.93 (m, 3H), 1.86-1.75 (m, 6H). 209^(m) piperidine FN 403.0(MeOD-d4) 8.06 (d, J = 9.6 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.33-7.22(m, 3H), 6.76 (d, J = 9.6 Hz, 1H), 4.46-4.37 (m, 1H), 4.33-4.24 (m, 2H),3.58-3.51 (m, 4H), 3.40-3.28 (m, 2H), 3.11 (s, 2H), 1.83-1.75 (m, 1H),1.73-1.62 (m, 8H), 1.58-1.50 (m, 1H). 210^(n) 1,2,3,4- FC 428.1(MeOD-d4) 7.83 (s, 1H), 7.53 (d, J = 7.2 tetrahydroquinoline Hz, 1H),7.43-7.36 (m, 3H), 6.98 (d, J = 7.2 Hz, 1H), 6.91-6.89 (m, 1H), 6.65 (t,J = 7.2 Hz, 1H), 6.40 (d, J = 8.0 Hz, 1H), 4.48 (s, 1H), 4.34 (br d, J =13.6 Hz, 1H), 4.19 (br d, J = 14.0 Hz, 1H), 3.60- 3.48 (m, 4H), 3.22 (d,J = 4.8 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 2.09-1.72 (m, 6H). ^(a)RuPhosand RuPhos-Pd-G2 or RuPhos with Pd₂(dba)₃ with Cs₂CO₃ or NaOtBu as thebase, or XantPhos-Pd-G4 with Pd₂(dba)₃ and Cs₂CO₃ could also be used asthe catalyst system for coupling in Step a. Step a ran from 2-16 h from80-110° C. Step 2 ran from 2-6 h from 25-60° C. in MeOH or EtOAc.^(b)Compound is racemic. ^(c)Compound is a mixture of diastereomers.^(d)Bromide not Iodide was used in Step a. ^(e)Chloride not Iodide usedin Step a. ^(f)TFA was used in Step b for the deprotection. ^(g)Step autilized Cs₂CO₃ and XantPhos-Pd-G4 in toluene for 100° C. for 12 h. ForStep b, TFA and TfOH (10:1) at 100° C. for 16 h was used to accomplishthe deprotection. ^(h)Step a was run with BrettPhos-Pd-G3 and NaOtBu intolune at 100° C. for 16 h. ^(i)Sphos-G4 withCs₂CO₃ in dioxane was usedfor Step a, which was run at 90° C. for 12 h. ^(j)No deprotection Step brequired. ^(k)RuPhos-Pd-G4, RuPhos, Cs₂CO₃, and NaI at 120° C. in tolunewere used in Step a for 12 h. ^(l)CPhos-Pd-G3 was used as the catalystwith tBuON in tolune at 90° C. were used in Step a for 12 h.^(m)tBuXPhos-Pd-G3 with tBuXPhos and tBuONa in tBuOH was used in Step ain tBuOH at 70 C. for 12 h. ^(n)TFA and TfOH at 100° C. was used fordeprotection in Step b.

Compounds Synthesized in Similar Fashion to Method 4 Example 65:Synthesis of1-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinolin-6-ylsulfurofluoridate

Step a:

A solution of tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(400.0 mg, 634.0 μmol, Intermediate J), 1,2,3,4-tetrahydroquinolin-6-ylacetate (240.0 mg, 1.26 mmol, Intermediate BI), XantPhos-Pd-G4 (60.9 mg,63.4 umol) and Cs₂CO₃ (206.0 mg, 634.0 umol) in toluene (15.0 mL) wasstirred at 85° C. for 12 hours under N₂. The reaction mixture wasconcentrated under reduced pressure. The mixture was triturated with H₂O(80.0 mL) and extracted with EtOAc (80.0 mL×2). The combined organiclayers were washed with brine (50.0 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give the product of1-{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinolin-6-ylacetate (450.0 mg, quant. crude yield) as a brown solid. LCMS m/z(M+H)⁺=694.3.

Step b:

A solution of1-{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinolin-6-ylacetate (450.0 mg, 648.0 μmol) in 2 N NaOH/MeOH (10.0 mL/20.0 mL) wasstirred at 20° C. for 0.5 hour. Then the reaction mixture was adjustedpH=5 with 2 N HCl. The reaction mixture was poured into H₂O (80.0 mL)and extracted with EtOAc (80.0 mL×2). The combined organic layers werewashed with brine (60.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give an orange residue. The residue was purified byflash silica gel chromatography (24 g column, Ethyl acetate in petroleumether from 0% to 30%) to give tert-butylN-[(3S)-1′-[3-(6-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(400.0 mg, 95% yield) as a yellow oil. LCMS m/z (M+H)⁺=652.2.

Step c:

A solution of tert-butylN-[(3S)-1′-[3-(6-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(350.0 mg, 536.0 μmol),[(4-acetamidophenyl)(fluorosulfonyl)amino]sulfonyl fluoride (252.0 mg,804.0 μmol, Intermediate BJ) and DBU (173.0 uL, 1.17 mmol) in THF (9.0mL) was stirred at 20° C. for 12 hours. The reaction mixture was thenpoured into H₂O (50.0 mL) and extracted with EtOAc (50.0 mL×2). Thecombined organic layers were washed with brine (50.0 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a yellow residue.The residue was purified by flash silica gel chromatography (12 gcolumn, ethyl acetate in petroleum ether from 0% to 20%) to give1-(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-6-ylsulfofluoridate (250.0 mg, 64% yield) as a yellow solid. LCMS m/z(M+H)⁺=734.2.

Step d:

A solution of1-(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-6-ylsulfurofluoridate (230.0 mg, 313.0 μmol) in HCl/MeOH (20.0 mL, 4 M) wasstirred at 20° C. for 0.5 hour. The reaction mixture was concentratedunder reduced pressure to give a residue, which was diluted with MeOH(5.0 mL) and purified by prep-HPLC (HCl) to give1-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}-1,2,3,4-tetrahydroquinolin-6-ylsulfurofluoridate hydrochloride (115.2 mg, 623% yield) as an orangesolid. LCMS m/z (M+H)⁺=550.1; ¹HNMR (400 MHz, CD₃OD): 8.30 (s, 1H),7.52-7.55 (m, 1H), 7.41-7.44 (m, 2H), 7.36-7.39 (m, 1H), 7.17-7.19 (m,1H), 6.95-7.00 (m, 2H), 4.52-4.56 (m, 1H), 4.40-4.44 (m, 2H), 3.94-3.98(m, 2H), 3.39-3.52 (m, 2H), 3.19-3.24 (m, 2H), 2.94-2.98 (m, 2H),2.12-2.16 (m, 2H), 1.81-1.94 (m, 3H), 1.66-1.70 (m, 1H).

Example 211: Synthesis of{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)pyrazin-2-yl}methanol

Step c:

Methyl3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)pyrazine-2-carboxylate(100 mg, 212 μmol, synthesized via Method 4, using methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate,Intermediate DN and 1,2,3,4-tetrahydro-1,5-naphthyridine in the couplingin Step a with Xantphos-Pd-G4 and Cs₂CO₃ as reactants; and running Stepb deprotection at rt for 2 h) and LiBH₄ (12.0 mg, 318 μmol) were placedinto THF (6 mL) and MeOH (4 mL). The reaction mixture was stirred at 20°C. for 12 hours. The mixture was then concentrated and was purified byprep-HPLC (HCOOH) to afford{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)pyrazin-2-yl}methanol(4.00 mg, 4% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 443.1 (M+H)⁺;¹HNMR (400 MHz, Methanol-d₄) δ 8.68-8.44 (m, 1H), 8.68-8.42 (m, 1H),8.15 (s, 1H), 8.00 (m, 1H), 7.65 (m, 1H), 7.36-7.26 (m, 3H), 7.19-7.07(m, 1H), 4.71 (s, 2H), 4.28 (s, 1H), 3.89 (m, 2H), 3.52-3.36 (m, 2H),3.22-3.08 (m, 4H), 3.05-2.96 (m, 3H), 2.20-2.10 (m, 2H), 2.07-1.92 (m,2H), 1.74-1.59 (m, 2H).

Example 212: Synthesis of{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(1,2,3,4-tetrahydroquinolin-1-yl)pyrazin-2-yl}methanol

Step c:

Methyl-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(1,2,3,4-tetrahydroquinolin-1-yl)pyrazine-2-carboxylate(30 mg, 63.8 μmol, synthesized via Method 4, usingmethyl-6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate,Intermediate DN and 1,2,3,4-tetrahydroquinoline in the coupling in Stepa with Xantphos-Pd-G4 and Cs₂CO₃ as reactants; and running Step bdeprotection at rt for 0.5 h) and LiBH₄ (2.79 mg, 127 μmol) were placedinto THE (5 mL). The reaction mixture was stirred at 30° C. for 2 hours.The mixture was then concentrated and was purified by prep-HPLC (HCOOH)to afford{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(1,2,3,4-tetrahydroquinolin-1-yl)pyrazin-2-yl}methanol(5.30 mg, HCOOH salt, 17% yield) as a yellow solid. LC-MS (ESI⁺) m/z:442.1 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄) δ=8.56 (s, 1H), 8.14 (s, 1H),7.46 (m, 1H), 7.37-7.25 (m, 3H), 7.24-7.13 (m, 2H), 7.12-7.04 (m, 1H),6.99-6.89 (m, 1H), 4.71 (s, 2H), 4.23 (s, 1H), 3.96-3.86 (m, 2H),3.30-3.20 (m, 2H), 3.20-3.05 (m, 3H), 3.04-2.91 (m, 1H), 2.83 (m, 2H),2.08-1.91 (m, 4H), 1.64 (m, 2H).

Example 213: Synthesis of(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(indolin-1-yl)pyrazin-2-yl)methanol

Step b:

To a solution of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(2,3-dihydro-1H-indol-1-yl)pyrazine-2-carboxylate(178 mg, 320 μmol, synthesized via Method 4, coupling methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate,Intermediate DN, with indoline in Step a using XantPhos-Pd-G4 and Cs₂CO₃in PhMe at 100° C. for 12 h) in THE (10 mL) was added DIBAL-H (480 μL,480 μmol, 1M in toluene) at 0° C. under N₂. The solution was stirred foranother 2 hours at the same temperature. Then to the reaction mixturewas added EtOAc (20 mL) and 10% AcOH (50 mL) slowly, then the solutionwas extracted with EtOAc (50 mL×3). The combined organic layers werewashed with aq. NaHCO₃ followed by brine (50 mL×3), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (ethyl acetate/petroleumether=0/100 to 30/100) to afford tert-butylN-[(3S)-1′-[5-(2,3-dihydro-1H-indol-1-yl)-3-(hydroxymethyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(64.0 mg, 38% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 528.1 (M+H)⁺.

Step c:

Tert-butylN-[(3S)-1′-[5-(2,3-dihydro-1H-indol-1-yl)-3-(hydroxymethyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 94.7 μmol) was dissolved in EtOAc (1.00 mL). HCl/EtOAc (1.00mL, 4 N) was then added and the mixture was stirred at 10° C. for 2 h.The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved with MeOH (5.0 mL) and adjusted to pH=7-8 withsolid Na₂CO₃ and purified by prep-HPLC (HCOOH).(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(indolin-1-yl)pyrazin-2-yl)methanol formate (31.4 mg, 70% yield) was obtained as a yellow solid.LC-MS (ESI+) m/z: 428.1 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄) δ 8.55 (s,1H), 8.26 (m, 1H), 7.92 (s, 1H), 7.52 (m, 1H), 7.43-7.28 (m, 3H),7.25-7.05 (m, 2H), 6.95-6.82 (m, 1H), 4.85-4.73 (m, 2H), 4.39 (s, 1H),4.10 (m, 2H), 3.31-3.19 (m, 4H), 3.18-3.06 (m, 4H), 2.12-1.81 (m, 2H),1.80-1.53 (m, 2H).

Example 214: Synthesis of(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)pyrazin-2-yl)methanol

Step a:

A solution of methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(800.0 mg, 1.5 mmol), Xantphos-Pd-G4 (147.0 mg, 154 μmol, IntermediateDN), Cs₂CO₃ (1.00 g, 3.08 mmol) and2,3,4,5-tetrahydro-1H-benzo[b]azepine (226.0 mg, 1.5 mmol, CAS#1701-57-1) in toluene (25.00 mL) was stirred at 100° C. for 12 hoursunder N₂. The mixture was concentrated and purified by flash silica gelchromatography (petroleum ether:EtOAc=100:0 to 100:20) to afford methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)pyrazine-2-carboxylate(267.0 mg, 30% yield) as a green oil. LC-MS (ESI⁺) m/z: 584.3 (M+H)⁺.

Step b:

To a solution of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)pyrazine-2-carboxylate(265.0 mg, 453 μmol) in THE (10.00 mL) was added DIBAL-H (679 μL, 679μmol, 1M in toluene) at 0° C. under N₂. The solution was stirred foranother 2 hours at the same temperature. To the reaction mixture wasadded EtOAc (20 mL) and 10% AcOH (50 mL) slowly, then the solution wasextracted with EtOAc (50 mL×3). The combined organic layers were washedwith aq. NaHCO₃ (50 mL), followed by brine (50 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (ethylacetate/petroleum ether=0/100 to 20/100) to afford tert-butylN-[(3S)-1′-[3-(hydroxymethyl)-5-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(166.0 mg, 66% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 556.2 (M+H)⁺.

Step c:

Tert-butylN-[(3S)-1′-[3-(hydroxymethyl)-5-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(90.0 mg, 161 μmol) was added into HCl/EtOAc (8.00 mL, 4M). The mixturewas stirred at 10° C. for 2 hours. The residue was then dissolved withMeOH (5.00 mL) and adjusted to pH=7-8 with solid Na₂CO₃ and purified byprep-HPLC (HCOOH).(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)pyrazin-2-yl)methanolformate salt (15.4 mg, 19% yield) was obtained as a yellow solid. LC-MS(ESI+) m/z: 456.1 (M+H)⁺; ¹H NMR (400 MHz, Methanol-d₄) δ=8.56 (s, 1H),7.47 (m, 1H), 7.41-7.37 (m, 1H), 7.37-7.22 (m, 7H), 4.73 (s, 2H), 4.26(s, 1H), 4.10-3.67 (m, 2H), 3.18-2.93 (m, 6H), 2.78-2.64 (m, 2H),2.03-1.82 (m, 4H), 1.81-1.56 (m, 4H).

Method 5, Examples 66 and 67: Synthesis of(3R)-1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amineand(3S)-1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To a solution of (2-chloro-3-fluoropyridin-4-yl)boronic acid (99.9 mg,570.0 μmol) tert-butylN-{1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(300.0 mg, 475.0 μmol, Intermediate F) in dioxane (10.0 mL) and H₂O (1.0mL) was added Pd(dppf)Cl₂ (34.7 mg, 47.5 μmol) and Cs₂CO₃ (462.0 mg, 1.4mmol), and the resulting mixture was stirred at 100° C. for 12 hoursunder N₂. The reaction mixture was then concentrated, diluted with EtOAc(100.0 mL), and washed with H₂O (50.0 mL×2) and brine (50.0 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue, which was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether=0˜30%) toafford tert-butyl(1′-(3-(2-chloro-3-fluoropyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(135.0 mg, 45% yield) as a yellow solid. LCMS m/z (M+H)⁺=634.2.

Step b:

Tert-butylN-{1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(100.0 mg, 0.158 mmol) was dissolved in HCl/MeOH (5.0 mL, 4N) andstirred at 20° C. for 12 hours. The mixture was then concentrated underreduced pressure to give a residue, which was diluted with MeOH (10.0mL) and adjusted pH=8˜9 with solid K₂CO₃. The mixture was filtered andconcentrated under reduced pressure to give a residue, which waspurified by flash silica gel chromatography (MeOH in DCM=0˜8%) to afford1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (40.0 mg, 56% yield) as a yellow solid. LCMS m/z(M+H)⁺=430.0.

Step c:

1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(40.0 mg, 88.9 μmol) was separated by preparative chiral SFC (Column:DAICEL CHIRALPAK IC (250 mm×30 mm, 5 um). Condition: 0.1% NH₃.H₂O EtOH.Begin: 50%, end: 50%. Flow rate: 50 mL/min.) to afford(3R)-1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(5.70 mg, 12.6 μmol, the faster eluting isomer, R_(t)=4.410 min, 14%yield, e.e. =100.0%) as a white solid and(3S)-1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(5.20 mg, 11.5 μmol, the slower eluting isomer, R_(t)=4.957 min, 13%yield, e.e. =96.7%) as a white solid. Absolute stereochemistry of theenantiomers was arbitrarily assigned. Characterization data for(3R)-1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine:LCMS m/z (M+H)⁺=450.1; ¹HNMR (400 MHz, DMSO-d₆): 8.52-8.60 (m, 1H),8.32-8.43 (m, 2H), 7.27-7.33 (m, 1H), 7.10-7.23 (m, 1H), 4.28-4.44 (m,1H), 3.85 (s, 1H), 3.21-3.27 (m, 2H), 3.10 (d, J=15.6 Hz, 1H), 2.65 (d,J=15.6 Hz, 1H), 1.77-1.87 (m, 1H), 1.64-1.76 (m, 1H), 1.50-1.61 (m, 1H),1.09-1.19 (m, 1H). SFC: e.e. =100%, Characterization data for(3S)-1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine:LCMS m/z (M+H)⁺=450.1; ¹HNMR (400 MHz, DMSO-d₆): 8.55-8.59 (m, 1H),8.34-8.42 (m, 2H), 7.25-7.33 (m, 1H), 7.12-7.24 (m, 1H), 4.28-4.45 (m,1H), 3.85 (s, 1H), 3.20-3.28 (m, 2H), 3.10 (d, J=15.6 Hz, 1H), 2.65 (d,J=15.6 Hz, 1H), 1.77-1.89 (m, 1H), 1.65-1.76 (m, 1H), 1.50-1.61 (m, 1H),1.09-1.19 (m, 1H). SFC: e.e. =96.7%.

Method 5 Table: Compounds synthesized via Method 5, with thecross-coupling of tert-butyl(1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(Intermediate F) with Various Boronic Acids in Step a

LCMS Example Step a m/z #^(a) Boronic Acid (M + H)⁺ ¹H NMR (400 MHz,CD3OD) δ ppm 68 (quinolin-5-yl)- 448.2 (CDCl3) 12.46 (br, 1H), 9.12 (d,J = 8.4 Hz, boronic 1H), 8.88-8.85 (m, 1H), 8.25-8.18 (m, 2H), acid 8.07(d, J = 8.4 Hz, 1H), 7.79-7.74 (m, 1H), 7.39-7.36 (m, 1H), 7.29-7.27 (m,1H), 7.17- 7.15 (m, 3H), 4.31-4.26 (m, 2H), 3.95 (s, 1H), 3.33-3.23 (m,2H), 3.07 (d, J = 17.6 Hz, 1H), 2.73-2.68 (m, 1H), 1.90-1.73 (m, 2H),1.62-1.58 (m, 1H), 1.39-1.35 (m, 1H). 69 (quinolin-5-yl)- 448.2 (DMSO)9.23 (d, J = 8.0 Hz, 1H), 8.98-8.95 boronic (m, 1H), 8.53 (s, 1H), 8.37(d, J = 6.4 Hz, acid 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.93-7.89 (m, 1H),7.61-7.58 (m, 1H), 7.32-7.31 (m, 1H), 7.22-7.14 (m, 3H), 4.42-4.35 (m,2H), 3.86 (s, 1H), 3.30-3.26 (m, 2H), 3.13 (d, J = 15.6 Hz, 1H), 2.66(m, J = 15.2 Hz, 1H), 1.90- 1.69 (m, 1H), 1.60-1.56 (m, 1H), 1.17-1.14(m, 1H). 70 (2,3-dichloropyridin- 466.1 8.47-8.42 (m, 2H), 7.84 (d, J =4.8 Hz, 1H), 4-yl)- 7.54 (d, J = 7.6 Hz, 1H), 7.44-7.34 (m, 3H), boronicacid 4.60-4.38 (m, 3H), 3.53-3.41 (m, 2H), 3.24 (CAS# 951677-39-7) (s,2H), 1.98-1.68 (m, 4H). 71 (2,3-dichloropyridin- 66.1 8.48-8.43 (m, 2H),7.84 (d, J = 4.4 Hz, 1H), 4-yl)- 7.56 (d, J = 7.2 Hz, 1H), 7.45-7.34 (m,3H), boronic acid 4.59-4.43 (m, 3H), 3.52-3.41 (m, 2H), 3.25 (CAS# (d, J= 6.0 Hz, 2H), 2.01-1.67 (m, 4H). 951677-39-7) 72 6-fluoro-5- 454.2 8.63(s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 7.54 (4,4,5,5- (d, J = 7.6 Hz, 1H),7.47-7.34 (m, 5H), tetramethyl- 6.62-6.61 (m, 1H), 4.67-4.51 (m, 2H),4.46 1,3,2-dioxaborolan- (s, 1H), 3.60-3.49 (m, 2H), 3.26 (s, 2H),2-yl)- 2.02-1.71 (m, 4H). 1H-indole (CAS # 1207623-96-8) 73 6-fluoro-5-454.2 8.62 (s, 1H), 8.51 (d, J = 6.8 Hz, 1H), 7.54 (4,4,5,5- (d, J = 7.2Hz, 1H), 7.47-7.34 (m, 5H), tetramethyl- 6.62-6.61 (m, 1H), 4.66-4.46(m, 3H), 3.60- 1,3,2-dioxaborolan- 3.49 (m, 2H), 3.26 (s, 2H), 2.01-1.71(m, 2-yl)- 4H). 1H-indole (CAS # 1207623-96-8) 74 (3-fluropyridin- 416.19.15-9.19 (m, 1H), 9.04-9.06 (m, 1H), 4-yl)- 8.77-8.79 (m, 1H), 8.59 (s,1H), 7.53-7.56 boronic acid (m, 1H), 7.41-7.47 (m, 2H), 7.35-7.39 (m,(CAS# 458532-97-3) 1H), 4.58-4.62 (m, 1H), 4.46-4.55 (m, 1H), 4.45 (s,1H), 3.43-3.54 (m, 2H), 3.25 (s, 2H), 1.82-2.00 (m, 3H), 1.69-1.73 (m,1H), 75 (3-fluropyridin- 416.1 9.35-9.55 (m, 1H), 9.07-9.08 (m, 1H),8.79- 4-yl)boronic 8.80 (m, 1H), 8.59 (s, 1H), 7.53-7.56 (m, acid 1H),7.42-7.46 (m, 2H), 7.34-7.39 (m, 1H), (CAS# 458532-97-3) 4.58-4.62 (m,1H), 4.46-4.55 (m, 1H), 4.45 (s, 1H), 3.43-3.54 (m, 2H), 3.25 (s, 2H),1.83-2.00 (m, 3H), 1.68-1.72 (m, 1H). 76 (2,3-dichlorophenyl) 481.08.53-8.64 (m, 5H), 7.50-7.51 (m, 1H), 7.36- boronic acid 7.48 (m, 6H),4.61-4.71 (m, 2H), 4.42-4.44 (m, 1H), 3.49-3.80 (m, 1H), 3.41 (s, 4H),3.04-3.09 (m, 1H), 1.90-1.95 (m, 2H), 1.69- 1.73 (m, 2H). ^(a)OtherSuzuki coupling conditions could be utilized such as Pd₂(dba)₃, XPhos(30.2 mg, 63.4 μmol) and K₃PO₄. Step b run anywhere from 1-12 hr at rt.Absolute stereochemistry of the enantiomers was arbitrarily assigned.^(b)tert-butyl(S)-(1′-(7-bromothieno[3,2-d]pyrimidin-4-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(Intermediate CW) was used in place of Intermediate F for the crosscoupling. The compound was chiral, no Step c was required.

Compounds Synthesized in Similar Fashion to Method 5 Examples 77 & 78:Synthesis of(R)-1′-(3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(SM-1′-(3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of tert-butylN-{1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(200.0 mg, 317.0 μmol, Intermediate F), (3-chloro-2-fluorophenyl)boronicacid (82.8 mg, 475.0 μmol), Pd(dppf)Cl₂ (34.7 mg, 47.5 μmol) and Na₂CO₃(67.2 mg, 634.0 μmol) in dioxane (10.0 mL) and H₂O (2.0 mL) was stirredat 100° C. for 12 hours. The mixture was concentrated, extracted withEtOAc (50.0 mL×3) and washed with brine (50.0 mL). The organic phase wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue, which was purified by flash silica gelchromatography (ethyl acetate in petroleum ether=0˜15%) to affordtert-butylN-{1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(70.0 mg, 35% yield) as a yellow solid. LCMS m/z (M+Na)⁺=656.2.

Step b:

The mixture of tert-butylN-{1′-[3-(2-chloro-3-fluoropyridin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(130.0 mg, 204.0 μmol), Pd₂(dba)₃ (18.6 mg, 20.4 μmol),diphenylmethanimine (55.4 mg, 306.0 μmol), Cs₂CO₃ (199.0 mg, 612.0 μmol)and BINAP (25.4 mg, 40.8 μmol) in toluene (5.0 mL) was evacuated andrefilled 3 times using N₂, the reaction mixture was stirred at 100° C.for 12 hours. The combined mixture was concentrated, extracted withEtOAc (50.0 mL×2) and washed with brine (50.0 mL). The organic phase wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue, which was purified by flash silica gelchromatography (ethyl acetate in petroleum ether=0˜35%) to affordtert-butylN-[1′-(3-{2-[(diphenylmethylidene)amino]-3-fluoropyridin-4-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 62% yield) as a yellow solid. LCMS m/z (M+H)⁺=779.4.

Step c:

To a solution of tert-butyl(1′-(3-(2-((diphenylmethylene)amino)-3-fluoropyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(120.0 mg, 154.0 μmol) in MeOH (2.0 mL) was added HCl/MeOH (2.0 mL, 4N)and the mixture was stirred at 20° C. for 12 hours. The mixture wasconcentrated to give a residue, which was washed with DCM/petroleumether (1/2, 5.0 mL×3). The solid was dried under vacuum to give1′-(3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(70.0 mg, quant. crude yield) as a yellow solid. LCMS m/z (M+H)⁺=431.1.

Step d:

1′-[3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(70.0 mg, 162.0 μmol) was separated by preparative SFC (column: DAICELCHIRALPAK AS-H (250 mm*30 mm, 5 um), Mobile phase: 0.1% NH₃.H₂O EtOH(Begin B: 55%, End B: 55%), Flow rate: 50 mL/min) to afford(R)-1′-(3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(16.6 mg, R_(t)=4.631 min, the faster eluting isomer) as a white solidand(S)-1′-(3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(13.8 mg, R_(t)=5.070 min, the slower eluting isomer) as a white solid.Characterization of(R)-1′-(3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z (M+H)⁺=431.1; ¹HNMR (400 MHz, Methanol-d₄): 8.38 (s, 1H), 7.81(d, J=5.2 Hz, 1H), 7.33-7.41 (m, 2H), 7.16-7.26 (m, 3H), 4.34-4.49 (m,2H), 3.95 (s, 1H), 3.33-3.45 (m, 2H), 3.17 (d, J=15.6 Hz, 1H), 2.81 (d,J=15.6 Hz, 1H), 1.74-1.96 (m, 2H), 1.57-1.70 (m, 1H), 1.41-1.51 (m, 1H).SFC: e.e. =98.7%. Characterization of(S)-1′-(3-(2-amino-3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z (M+H)⁺=431.1; ¹HNMR (400 MHz, Methanol-d₄): 8.52 (s, 1H), 7.96(t, J=6.2 Hz, 1H), 7.80 (d, J=6.4 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H),7.38-7.45 (m, 2H), 7.31-7.38 (m, 1H), 4.52-4.62 (m, 1H), 4.39-4.50 (m,2H), 3.37-3.55 (m, 2H), 3.23 (s, 2H), 1.90-2.01 (m, 1H), 1.76-1.89 (m,2H), 1.63-1.74 (m, 1H). SFC: e.e. =97.2%, Column: Chiralpak AS-H 150*4.6mm I.D., 5 um, Mobile phase: A: CO₂ B: ethanol (0.05% DEA), Gradient:hold 5% for 0.5 min, then from 5% to 40% of B in 3.5 min and hold 40%for 2.5 min, then 5% of B for 1.5 min, Flow rate: 3 mL/min, Columntemperature: 40° C.

Example 79: Synthesis of(3S)-1′-[3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

(3S)-1′-[3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride was synthesized as described above for Example 77,coupling tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(Intermediate J) and (2,3-dichloropyridin-4-yl)boronic acid in Step a.No chiral separation was required as the amine was chiral.(3S)-1′-[3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (29.3 mg, 54% yield) was isolated as a yellow solid. LCMSm/z (M+H)⁺=447.1; ¹HNMR (400 MHz, Methanol-d₄): δ 8.50 (s, 1H), 7.99 (d,J=6.8 Hz, 1H), 7.63 (d, J=6.8 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.46-7.34(m, 3H), 4.60-4.44 (m, 3H), 3.54-3.41 (m, 2H), 3.24 (s, 2H), 2.04-1.68(m, 4H). SFC: e.e. =94.0%, R_(t)=5.008 min, Column: Chiralpak AS-H150×4.6 mm I.D., 5 um Mobile phase: A: CO₂ B: ethanol (0.1%ethanolamine) Gradient: hold 5% for 0.5 min, then from 5% to 40% of B in3.5 min and hold 40% for 2.5 min, then 5% of B for 1.5 min, Flow rate: 3mL/min Column temp: 40° C.

Method 6, Examples 80 & 81: Synthesis of(R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineand(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

The compounds of 2,5-dibromopyrazine (500 mg, 2.1 mmol),1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride (815 mg,2.5 mmol, Intermediate E) and TEA (1.5 mL, 10.5 mmol) were added in DMF(20 mL) and the mixture was stirred at 85° C. for 12 h. The mixture wasthen diluted with ethyl acetate (100 mL). The mixture was washed withH₂O (20 mL×3) and brine (30 mL×3), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (DCM:MeOH=100:0 to 100:5) to afford1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(740 mg, 98% yield) as a yellow oil.

Step b:

The compounds of1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(200 mg, 0.5 mmol), sodium 2-amino-3-chloropyridine-4-thiolate (131 mg,0.7 mmol, Intermediate AC), Pd₂(dba)₃ (51 mg, 0.05 mmol), XantPhos (64mg, 0.1 mmol), DIPEA (0.5 mL, 2.8 mmol) were added in dioxane (10 mL).The reaction mixture was evacuated and refilled 3 times using N₂. Thereaction mixture was stirred at 110° C. for 12 hours. The mixture wasfiltered and the filtrate was concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether:ethyl acetate=100:20 to 100:100 then EtOAc:MeOH=100:5) to afford1′-{5-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(150 mg, 61% yield) as a yellow solid. LCMS m/z (M+H)⁺=439.1.

Step c:

The compoundrac-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(150 mg, 341 μmol) was separated by Chiral-SFC (Column: DAICEL CHIRALCELOD (250 mm*30 mm, 10 um)). Mobile phase: 55% of MeOH (0.1% NH₃.H₂O) inCO₂. Flow rate: 70 mL/min.) to afford(R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(43.5 mg, 29% yield, R_(t)=1.546 min, the faster eluting isomer) as anoff-white solid and(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(46.5 mg, 31% yield, R_(t)=1.982 min, the slower eluting isomer) as anoff-white solid. Absolute stereochemistry of the enantiomers wasarbitrarily assigned. Characterization of(R)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z (M+H)⁺=439.1; ¹HNMR (400 MHz, CD₃OD): δ 8.23 (s, 1H), 8.17 (s,1H), 7.49˜7.52 (m, 1H), 7.26˜7.28 (m, 1H), 7.09˜7.13 (m, 3H), 5.83˜5.85(m, 1H), 4.23˜4.27 (m, 2H), 3.88 (s, 1H), 3.24-3.29 (m, 2H), 3.05˜3.10(m, 1H), 2.72˜2.77 (m, 1H), 1.65˜1.81 (m, 2H), 1.51˜1.55 (m, 1H),1.35˜1.39 (m, 1H); SFC: e.e. =93.6%, R_(t)=1.546 min. Characterizationof(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z (M+H)⁺=439.1; ¹HNMR (400 MHz, CD₃OD): δ 8.35 (s, 1H), 8.29 (s,1H), 7.61˜7.64 (m, 1H), 7.38˜7.40 (m, 1H), 7.21˜7.26 (m, 3H), 5.95˜5.97(m, 1H), 4.35˜4.38 (m, 2H), 3.98 (s, 1H), 3.37-3.40 (m, 2H), 3.17˜3.22(m, 1H), 2.82˜2.87 (m, 1H), 1.77˜1.94 (m, 2H), 1.63˜1.67 (m, 1H),1.46˜1.50 (m, 1H). SFC: e.e. =98.37%, R_(t)=1.982 min. Column: ChiralcelOD-3 50*4.6 mm I.D., 3 um. Mobile phase: 40% of methanol (0.05% DEA) inCO₂. Flow rate: 4 mL/min. Column temp: 40° C.

Example 82: Synthesis of(3R)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine

Step a:

A mixture of(R)—N-[(3R)-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(150.0 mg, 459 μmol, Intermediate CA), 2,5-dibromopyrazine (130.0 mg,550 μmol, CAS #23229-25-6) and TEA (316 μL, 2.3 mmol) in DMF (10 mL) wasstirred at 80° C. for 12 hours. The mixture was diluted with H₂O (25mL), then extracted with ethyl acetate (30 mL×2). The organic phaseswere washed with brine (15 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (ethyl acetated in petroleum ether=0% to 60%)to afford(R)—N-[(3R)-1′-(5-bromopyrazin-2-yl)-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(180.0 mg, 81% yield) as a yellow oil. LCMS m/z (M+H)⁺=482.9, 484.9.

Step b:

A mixture of(R)—N-[(3R)-1′-(5-bromopyrazin-2-yl)-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(180.0 mg, 372 μmol), 2,3-dichloro-4-(sodiosulfanyl)pyridine (90.1 mg,446 μmol, Intermediate AV), Pd₂(dba)₃ (34.0 mg, 37.2 μmol), XantPhos(43.0 mg, 74.4 μmol) and DIPEA (182 μL, 1.1 mmol) in 1,4-dioxane (10.0mL) was stirred at 110° C. for 12 hours under N₂ atmosphere. Thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 80%) to afford(R)—N-[(3R)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(150 mg, 69% yield) as a yellow oil. LCMS m/z (M+H)⁺=582.0.

Step c:

A mixture of(R)—N-[(3R)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(140.0 mg, 240 μmol) in HCl/MeOH (4M, 10 mL) was stirred at 25° C. for0.5 hours. The mixture was concentrated under reduced pressure to give aresidue, which was purified by prep-HPLC (HCl) to afford(3R)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-7-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride (84.1 mg, 68% yield) as a yellow solid. LCMS m/z(M+H)⁺=477.8; ¹HNMR (400 MHz, Methanol-d₄): δ 8.50 (d, J=0.8 Hz, 1H),8.39 (d, J=0.8 Hz, 1H), 8.04 (d, J=5.6 Hz, 1H),), 7.41 (d, J=7.6 Hz,1H), 7.30-7.25 (m, 1H), 7.11-7.06 (m, 1H), 6.76 (d, J=5.2 Hz, 1H),4.79-4.71 (m, 2H), 4.53-4.49 (m, 1H), 3.61-3.48 (m, 2H), 2.26-2.16 (m,2H), 2.06-1.91 (m, 2H).

Compounds Synthesized in a Similar Fashion to Method 6 Examples 83 & 84:Synthesis of(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineand(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(600 mg, 2.0 mmol, synthesized via Step a of Example 120),2,5-dibromo-3-methylpyrazine (586 mg, 2.3 mmol, CAS #1260672-37-4) andTEA (1.3 mL, 9.8 mmol) in DMF (15 mL) was stirred at 80° C. for 2 hours.The reaction mixture was diluted with ethyl acetate (40 mL), and washedwith H₂O (30 mL×2). The organic phase was washed with brine (10 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 70%) to afford(R)—N—((S)-1′-(5-bromo-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-1′-(5-bromo-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(380 mg, 3:1 ratio of(R)—N—((S)-1′-(5-bromo-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideto(R)—N—((S)-1′-(5-bromo-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide)as a white solid. LCMS m/z (M+H)⁺=477.0/479.0.

Step b:

A mixture of(R)—N—((S)-1′-(5-bromo-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-1′-(5-bromo-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(350 mg, 733 μmol), 3-chloro-4-(sodiosulfanyl)pyridin-2-amine (160 mg,879 μmol, Intermediate AC), Pd₂(dba)₃ (67.1 mg, 73.3 μmol), XantPhos(84.4 mg, 146 μmol) and DIPEA (391 mL, 2.2 mmol) in dioxane (15 mL) wasstirred at 110° C. for 12 hours under N₂ atmosphere. The reactionmixture was concentrated in vacuo to give a residue, which was purifiedby silica gel chromatography (Methanol in Dichloromethane=0% to 10%) toafford(R)—N—((S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(420 mg) as a brown solid. LCMS m/z (M+H)⁺=557.0.

Step c:

A mixture of(R)—N—((S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(350 mg, 628 μmol) in HCl/MeOH (4M, 5 mL) was stirred at 20° C. for 0.5hours. The mixture was concentrated under reduced pressure to give aresidue, which was purified by prep-HPLC (NH₃.H₂O) to afford(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineand(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(160 mg, mixed) as a yellow solid.

Step d:

The mixture of(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineand(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(160 mg) was separated by preparative SFC (column: DAICEL CHIRALCEL OJ-H(250 mm×30 mm, 5 um), Mobile phase: 0.1% NH₃.H₂O MeOH (Begin B: 40%, EndB: 40%), Flow rate: 60 mL/min) to afford the product of(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(99 mg, 35% yield, R_(t)=5.58 min, the slower eluting isomer) as a whitesolid and(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(32.9 mg, 12% yield, R_(t)=4.65 min, the faster eluting isomer) as awhite solid. Characterization of(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z (M+H)⁺=453.0; ¹HNMR (400 MHz, Methanol-d₄): δ 8.03 (s, 1H),7.49 (d, J=5.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.14-7.09 (m, 3H), 5.71 (d,J=5.2 Hz, 1H), 4.71-4.39 (m, 2H), 4.28-4.23 (m, 2H), 3.86 (s, 1H), 3.07(d, J=15.6 Hz, 1H), 2.71 (d, J=15.6 Hz, 1H), 2.34 (s, 3H), 1.80-1.64 (m,2H), 1.54-1.49 (m, 1H), 1.37-1.32 (m, 1H); SFC: e.e.=100%.Characterization of(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z (M+H)⁺=453.0; ¹HNMR (400 MHz, Methanol-d₄): δ 8.15 (s, 1H),7.51 (d, J=5.6 Hz, 1H), 7.29-7.27 (m, 1H), 7.11-7.09 (m, 3H), 5.88 (d,J=5.6 Hz, 1H), 3.88 (s, 1H), 3.63-3.59 (m, 2H), 3.12-3.01 (m, 3H), 2.69(d, J=15.6 Hz, 1H), 2.46 (s, 3H), 1.94-1.78 (m, 2H), 1.55-1.52 (m, 1H),1.39-1.36 (m, 1H). SFC: e.e.=95.5%; Chiralcel OJ-3 100×4.6 mm I.D., 3um; Mobile phase: A: CO₂, B: ethanol (0.05% DEA); Gradient: from 5% to40% of B in 4 min and hold 40% for 2.5 min, then 5% of B for 1.5 Min;Flow rate: 2.8 mL/min; Temperature: 35° C.

Method 7, Examples 85 & 86: Synthesis of(R)-1′-(3-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineand(S)-1′-(3-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

To a solution of tert-butyl(1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(200 mg, 317 μmol, Intermediate F) and sodium2-amino-3-chloropyridine-4-thiolate (86.7 mg, 475 μmol, Intermediate AC)in dioxane (5.0 mL) was added Pd₂(dba)₃ (29 mg, 31.7 μmol), XantPhos(36.6 mg, 63.4 μmol) and Cs₂CO₃ (206.0 mg, 634.0 μmol). The reactionmixture was purged with N₂ for 3 min, and the reaction was stirred at100° C. for 12 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatography(petroleum ether:ethyl acetate=100:0 to 100:70) and then prep-TLC(DCM:MeOH=10:1) to afford the product tert-butyl(1′-(3-((2-amino-3-chloropyridin-4-yl)thio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(120 mg, 57% yield) as a light yellow solid. LCMS m/z (M+H)⁺=663.1.

Step b:

A solution of tert-butyl(1′-(3-((2-amino-3-chloropyridin-4-yl)thio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(120 mg, 180 μmol) in HCl/MeOH (5.0 mL, 4M) was stirred at 15° C. for 1hour. The reaction mixture was concentrated under reduced pressure togive the product1′-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (85 mg, 92% yield). LCMS m/z (M+H)⁺=479.1.

Step c:

The compound of1′-(3-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(75 mg, 156 μmol) was separated by SFC to give each enantiomer crude.Conditions for separation: Column: DAICEL CHIRALPAK AS-H (250 mm×30 mm,5 um). Condition: 0.1% NH₃.H₂O EtOH. Begin B 50%, end B 50%. Flow rate:50 mL/min. Each enantiomer was then purified by prep-TLC(Dichloromethane:Methanol=10:1).(R)-1′-(3-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(30.0 mg, 40% yield) was obtained as a white solid. LCMS m/z(M+H)⁺=479.1; ¹HNMR (400 MHz, CDCl₃+CD₃OD): δ 8.20 (s, 1H), 7.45-7.47(m, 1H), 7.24-7.27 (m, 1H), 7.14-7.21 (m, 3H), 5.86-5.87 (m, 1H),4.26-4.29 (m, 2H), 3.92 (s, 1H), 3.23-3.28 (m, 2H), 3.02-3.06 (m, 1H),2.72-2.75 (m, 1H), 1.68-1.82 (m, 2H), 1.58-1.61 (m, 1H), 1.40-1.43 (m,1H). SFC: e.e. =96.2%, R_(t)=5.272 min.(S)-1′-(3-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(27.0 mg, 36% yield) was obtained as a white solid. LCMS m/z(M+H)⁺=479.1; ¹HNMR (400 MHz, CDCl₃+CD₃OD): δ 8.20 (s, 1H), 7.48-7.50(m, 1H), 7.27-7.28 (m, 1H), 7.17-7.20 (m, 3H), 5.88-5.89 (m, 1H),4.25-4.28 (m, 2H), 3.94 (s, 1H), 3.22-3.28 (m, 2H), 3.03-3.07 (m, 1H),2.71-2.75 (m, 1H), 1.69-1.84 (m, 2H), 1.58-1.62 (m, 1H), 1.39-1.43 (m,1H). SFC: e.e. =97.8%, R_(t)=5.808 min. Column: Chiralpak AS-3 100×4.6mm I.D., 3 m. Mobile phase: A: CO₂ B: ethanol (0.05% DEA). Gradient:from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 500 of Bfor 1 min. Flow rate: 2.8 mL/min, Column temperature: 40° C.

Method 7 Table: Compounds Synthesized Via Method 7, with theCross-Coupling of Sulfur Salts with Various Bromides or Iodides in Stepa

Step a LCMS Example Step a Iodide m/z #^(a) SNa salt or Bromide (M + H)⁺¹H NMR (400 MHz, CD₃OD) δ ppm  87^(b) AC BF 453.9 7.69 (s, 1H),7.64~7.67 (m, 1H), 7.52~7.55 (m, 1H), 7.36~7.44 (m, 3H), 6.27~6.29 (m,1H), 4.30~4.46 (m, 3H), 3.36~3.41 (m, 2H), 3.21 (s, 2H), 1.75- 1.93 (m,3H), 1.60~1.63 (m, 1H).  88^(b) AV K 528.0 (DMSO) 8.09 (s, 1 H) 7.50 (d,J = 5.71 Hz, 1 H) 5.69-5.80 (m, 1 H) 4.55 (s, 2 H) 4.17-4.25 (m, 1 H)3.83 (d, J = 9.34 Hz, 2 H) 3.61-3.77 (m, 4 H) 3.36 (d, J = 4.41 Hz, 1 H)2.87-3.07 (m, 2 H) 1.79-1.91 (m, 2H) 1.75 (br s, 1 H) 1.61 (br d, J =12.97 Hz, 1 H) 1.17 (d, J = 6.48 Hz, 3 H).  89^(b) AW K 508.3 (DMSO)8.09 (s, 1 H) 7.50 (d, J = 5.71 Hz, 1 H) 5.69-5.80 (m, 1 H) 4.55 (s, 2H) 4.17-4.25 (m, 1 H) 3.83 (d, J = 9.34 Hz, 2 H) 3.61-3.77 (m, 4 H) 3.36(d, J = 4.41 Hz, 1 H) 2.87-3.07 (m, 2 H) 1.79-1.91 (m, 2H) 1.75 (br s, 1H) 1.61 (br d, J = 12.97 Hz, 1 H) 1.17 (d, J = 6.48 Hz, 3 H).  90^(b) AWJ 478.1 8.46 (s, 1H), 8.22-8.24 (d, J = 6.4, 1H), 7.53-7.55 (d, J = 7.2,1H), 7.34-7.47 (m, 3H), 7.10-7.11 (d, J = 6.4, 1H), 4.56- 4.59 (m, 1H),4.43-4.47 (m, 2H), 3.43- 3.54 (m, 2H), 3.24 (s, 2H), 2.83 (s, 3H),1.81-1.99 (m, 3H), 1.68-1.71 (m, 1H).  91^(c) AV J 498.0 8.43 (s, 1H),7.93-7.95 (d, J = 5.2, 1H), 7.51-7.53 (d, J = 7.6, 1H), 7.35-7.46 (m,3H), 6.62-6.63 (d, J = 5.2, 1H), 4.54- 4.57 (m, 1H), 4.43-4.47 (m, 2H),3.43- 3.52 (m, 2H), 3.24 (s, 2H), 1.79-1.96 (m, 3H), 1.67-1.71 (m, 1H). 92 AV J 498.0 8.43 (s, 1H), 7.93-7.95 (d, J = 5.6, 1H), 7.51-7.53 (d, J= 7.2, 1H), 7.35-7.46 (m, 3H), 6.62-6.63 (d, J = 5.2, 1H), 4.54- 4.58(m, 1H), 4.43-4.47 (m, 2H), 3.43- 3.52 (m, 2H), 3.24 (s, 2H), 1.78-1.96(m, 3H), 1.67-1.71 (m, 1H).  93^(b) AC CK 439.0 (DMSO) 8.68 (br, 3H),8.52 (s, 2H), 7.84-7.81 (d, J = 6.8 Hz, 1H), 7.63-7.28 (m, 4H),6.30-6.28 (d, J = 6.8 Hz, 1H), 4.64-4.53 (m, 2H), 4.36-4.34 (m, 1H),3.33-2.99 (m, 4H), 1.82-1.52 (m, 4H).  94^(b) AV CL 460.0 8.48-8.49 (m,1H), 8.38-8.39 (m, 1H), 8.03-8.04 (d, J = 5.6 Hz, 1H), 7.56-7.58 (m,1H), 7.42-7.46 (m, 1H), 7.07-7.11 (m, 1H), 7.02-7.04 (m, 1H), 6.74-6.75(d, J = 5.2 Hz, 1H), 4.67-4.73 (m, 2H), 4.47-4.50 (m, 1H), 3.47-3.59 (m,2H), 2.11-2.20 (m, 2H), 1.85-1.97 (m, 2H).  95^(b) AJ CL 426.0 8.44-8.45(m, 1H), 8.37-8.38 (m, 1H), 7.99-8.00 (d, J = 5.2 Hz, 1H), 7.56-7.58 (m,1H), 7.42-7.46 (m, 1H), 7.07-7.11 (m, 1H), 7.01-7.04 (m, 1H), 6.92-6.94(m, 1H), 4.66-4.71 (m, 2H), 4.44-4.48 (m, 1H), 3.45-3.59 (m, 2H),2.12-2.16 (m, 2H), 1.84-1.97 (m, 2H).  96^(b) CT CL 426.0 8.39 (s, 1H),8.32(s, 1H), 8.19-8.22 (m, 1H), 7.55-7.58 (m, 1H), 7.41-7.47 (m, 2H),7.27-7.30 (m, 1H), 7.01-7.10 (m, 2H), 4.63-4.76 (m, 2H), 4.41-4.45 (m,1H), 3.44-3.54 (m, 2H), 2.08-2.15 (m, 2H), 1.86-1.96 (m, 2H).  97^(b) ACCU 438.0 8.45 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.67-7.63(m, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.44-7.42 (m, 3H), 4.45 (s, 3H),4.00-3.87 (m, 2H), 3.29-3.16 (m, 4H), 2.06-1.69 (m, 4H). 177^(b) AC CL440.9 8.50-8.51 (m, 1H), 8.40-8.41 (m, 1H), 7.65-7.67 (m, 1H), 7.56-7.58(m, 1H), 7.42-7.46 (m, 1H), 7.07-7.11 (m, 1H), 7.01-7.04 (m, 1H),6.36-6.38 (m, 1H), 4.68-4.74 (m, 2H), 4.48-4.52 (m, 1H), 3.47-3.60 (m,2H), 2.11-2.24 (m, 2H), 1.87-1.98 (m, 2H). 215^(b) AC DT 467.2 7.64 (d,J = 6.8 Hz 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.43-7.38 (m, 2H), 7.36-7.32(m, 1H), 6.27(d, J = 6.8 Hz 1H), 4.45 (s, 1H), 3.93 (d, J = 14 Hz, 1H),3.82 (d, J = 13.6 Hz 1H), 3.34 (d, J = 2.8 Hz 1H), 3.27-3.23 (m, 1H),3.19 (s, 2 H), 2.55 (d, 6H) 2.09-2.02 (m, 1H), 1.96-1.89, (m, 1H) 1.82(d, J = 13.2 Hz 1 H), 1.68 (d, J = 13.6 Hz, 1 H) 216^(b) AC EC 440.078.63 (s, 1H), 7.92-7.90 (m, 2H), 7.72 (d, J = 6.80 Hz, 1H), 7.58 (d, J= 7.60 Hz, 1H), 7.44-7.40 (m, 1H), 7.09-7.05 (m, 1H), 7.00 (d, J = 8.40Hz, 1H), 6.38 (d, J = 7.20 Hz, 1H), 4.70 (s, 1H), 4.24 (d, J = 13.6 Hz,1H), 4.04 (d, J = 12.4 Hz, 1H), 3.60-3.48 (m, 2H), 2.36-2.30 (m, 1H),2.14-2.11 (m, 1H), 2.05- 2.01 (m, 1H), 1.97-1.93 (m, 1H). 217^(b) AC DY456.2 8.61 (d, J = 2.00 Hz, 1H), 7 95-7 91 (m, 2H), 7.73 (d, J = 6.80Hz, 1H ), 7.56- 7.53 (m, 1H), 7.15-7.09 (m, 2H), 6.39 (d, J = 6.80 Hz,1H), 4.45 (s, 1H), 4.09 (d, J = 13.6 Hz, 1H), 3.98 (d, J = 14 Hz, 1H),3.45-3.39 (m, 2H), 3.26-3.17 (m, 2H), 2.09-2.04 (m, 1H), 2.03-1.93 (m,1H), 1.86 (d,J = 12.4 Hz, 1H), 1.72 (d, J = 13.2 Hz, 1H). 218^(b) AC EA456.0 8.63 (s, 1H), 7.98-7.93 (m, 2H), 7.74 (d, J = 6.80 Hz, 1H ),7.40-7.38 (m, 1H), 7.30-7.27 (m, 1H), 7.27-7.16(m, 1H), 6.41 (d, J =6.80 Hz, 1H), 4.49 (s, 1H), 4.12 (d, J = 13.6 Hz, 1H), 4.01 (d, J =14Hz, 1H), 3.45-3.38 (m, 2H), 3.23-3.12 (m, 2H), 2.07-1.98 (m, 2H), 1.83(d, J = 13.2 Hz, 1H), 1.74 (d, J = 12.8 Hz, 1H). 219^(b,d) AC DU 452.28.48 (d, J = 2.8 Hz 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.72 (d J = 7.2 Hz,1H), 7.53 (d, J = 7.2 Hz 1H), 7.44-7.34 (m, 3H), 6.27 (d, J = 7.2 Hz1H), 4.46 (s, 1H), 4.11 (d, J = 14 Hz 1H), 3.99 (d, J = 13.6 Hz 1H),3.44-3.36 (m, 2H), 3.26-3.16 (m, 2 H), 2.49 (s, 3H) 2.08-1.93 (m, 2H),1.83 (d, J = 12.8 Hz 1H), 1.71 (d, J = 12.8 Hz 1 H). 220^(b,e) AV DO466.0 8.54 (s, 2H), 8.10 (m, 1H), 7.50 (m, 1H), 7.41-7.30 (m, 3H), 6.93(m, 1H). 4.62 (m, 2H), 4.36 (s, 1H), 3.60 (m, 2H), 3.29-3.10 (m, 2H),2.08-1.86 (m, 2H), 1.83-1.68 (m, 2H) 221^(f) AC FV 469.0 8.03 (s, 1H),7.63-7.65 (m, 1H), 7.44- 7.46 (m, 1H), 7.19-7.24 (m, 1H), 6.91- 6.96 (m,1H), 6.76-6.79 (m, 1H), 6.06- 6.08 (m, 1H), 4.75-4.79 (m, 1H), 4.45-4.51 (m, 2H), 4.19-4.25 (m, 1H), 3.82- 3.85 (m, 1H), 3.15-3.22 (m, 1H),2.54- 2.58 (m, 1H), 1.94-2.08 (m, 3H), 1.60- 1.67 (m, 1H). 222^(f) AC FV469.0 8.09 (s, 1H), 7.68-7.71 (m, 1H), 7.59- 7.62 (m, 1H), 7.41-7.46 (m,1H), 7.08- 7.12 (m, 1H), 7.00-7.03 (m, 1H), 6.55- 6.57 (m, 1H), 4.76 (s,1H), 4.67-4.71 (m, 2H), 4.37-4.42 (m, 1H), 4.08-4.15 (m, 1H), 3.35-3.40(m, 1H), 2.14-2.20 (m, 2H), 1.98-2.02 (m, 2H). 223^(b) AC FH 498.1 7.69(d, J = 6.8 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.46-7.35 (m, 3H), 6.44(d, J = 6.8 Hz, 1H), 4.49 (s, 1H), 4.05-4.00 (m, 1H), 3.93-3.87 (m, 1H),3.61-3.50 (m, 2H), 3.27-3.18 (m, 2H), 2.49 (s, 3H), 2.08-1.92 (m, 2H),1.86-1.81 (m, 1H), 1.74-1.70 (m, 1H). 224^(b,d) AC FO 458.0 8.65 (d, J =2.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.73 (d, J = 7.2 Hz, 1H), 7.61-7.57 (m,1H), 6.87-6.79 (m, 2H), 6.38 (d, J = 7.2 Hz, 1H), 4.72 (s, 1H),4.28-4.20 (m, 1H), 4.09-4.00 (m, 1H), 3.60-3.48 (m, 2H), 2.38-2.32(m,1H), 2.17-1.97 (m, 3H). 225^(b,d) AC FP 458.0 8.57 (s, 1H), 7.82-7.66(m, 3H), 7.36- 7.30 (m, 1H), 7.21-7.15 (m, 1H), 7.01- 6.94 (s, 1H), 4.71(m, 1H), 4.22-4.11 (m, 1H), 4.03-3.94 (m, 1H), 3.55-3.99 (m, 2H),2.34-1.94 (m, 4H). ^(a)Step a was run anywhere from 100-120° C. for 12h. Step b ran anywhere from 1-12 h. ^(b)No SFC Step c was required asbromide or iodide utilized in the coupling was chiral. ^(c)For compoundsseparated via SFC, absolute stereochemistry of the enantiomers wasarbitrarily assigned. ^(d)DIPEA was used as the base in Step a.^(e)HCl/EtOAc (4M) was used for deprotection in Step b. ^(f)Step b wasran at 90° C. for 1 h. No SFC Step c required: the diastereomers wereseparated by prep-HPLC (HCl) and the absolute stereochemistry wasarbitrarily assigned.

Method 8, Example 98: Synthesis of(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(5-(methylsulfonyl)-3,4-dihydroquinolin-1(211)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

Step a:

A resealable reaction vial was charged with{6-[(1S)-1-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (100 mg, 0.1423 mmol, Intermediate K),5-methanesulfonyl-1,2,3,4-tetrahydroquinoline (33.0 mg, 0.1565 mmol),9-{[5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenyl-?5-phosphanyl}-8-methyl-8-aza-9-palladatricyclo[8.4.0.0²,7]tetradeca-1(14),2(7),3,5,10,12-hexaen-9-ylmethanesulfonate (13.6 mg, 0.01423 mmol), and dicesium (1+) carbonate(92.7 mg, 0.2846 mmol). The vial was evacuated and backfilled with N₂gas 3× then toluene (5 mL) was added and the reaction was stirred at 95°C. for 72 h. The reaction mixture was then pre-absorbed onto silica geland purified on by column chromatography (10 g column, using 0-100%EA/hep) to give{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-(5-methanesulfonyl-1,2,3,4-tetrahydroquinolin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (59.0 mg, 53% yield). LCMS m/z (M+H)⁺=786.4.

Step b:

Dissolved{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-(5-methanesulfonyl-1,2,3,4-tetrahydroquinolin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (92 mg, 0.117 mmol) in DCM (3 mL) and added TFA (1 mL) andstirred at rt for 16 h. Toluene was then added and the reaction mixturewas concentrated. The residue was then dissolved in THE (5 mL) andlithium (1+) hydroxide (1.17 mL, 1.17 mmol) (1N) was added and thereaction mixture was stirred at rt for 2 hr. The reaction mixture wasthen concentrated and the residue was dissolved in DMSO with additionalformic acid (65.9 μL, 1.75 mmol). The solution was purified by reversephase prep-HPLC (using 10-40% B (FA) to give{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-(5-methanesulfonyl-1,2,3,4-tetrahydroquinolin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol(18.0 mg, yield). LCMS m/z (M+H)⁺=560.2; ¹H NMR (400 MHz, DMSO-d6) δ12.86-13.16 (m, 1H), 7.33-7.39 (m, 2H), 7.11-7.24 (m, 5H), 4.54 (s, 2H),4.00 (s, 1H), 3.88-3.93 (m, 2H), 3.73-3.81 (m, 2H), 3.21-3.26 (m, 5H),3.04-3.17 (m, 3H), 2.71 (br d, J=15.87 Hz, 1H), 2.04 (quin, J=6.04 Hz,2H), 1.81-1.99 (m, 2H), 1.56 (br d, J=12.70 Hz, 1H), 1.27 (br d, J=12.94Hz, 1H).

Method 8 Table: Compounds Synthesized Via Method 8, with theCross-Coupling of(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylAcetate (Intermediate K) with Various Amines in Step a

LCMS Example Step a m/z #^(a) Amine (M + H)⁺ ¹H NMR (400 MHz, DMSO-d6) δppm  99^(b) 1,2,3,4- 483.2 8.27 (s, 1 H) 7.81-7.88 (m, 1 H) 7.45 (d, J =7.52 tetrahydro-1,5- Hz, 1 H) 7.30-7.38 (m, 3 H) 7.23-7.29 (m, 1 H)naphthyridine 6.95-7.01 (m, 1 H) 4.55 (s, 2 H) 4.31 (s, 1 H) 3.87-3.93(m, 2 H) 3.61-3.77 (m, 2 H) 3.05- 3.15 (m, 3 H) 2.94-3.02 (m, 1 H) 2.91(t, J = 6.48 Hz, 2 H) 1.99-2.08 (m, 2 H) 1.78-1.91 (m, 2 H) 1.59 (br d,J = 12.45 Hz, 1 H) 1.51 (br d, J = 12.45 Hz, 1 H). 100 1,2,3,4- 483.212.94 (br s, 1H), 8.16 (s, 1H), 7.91 (dd, J = 1.34, tetrahydro-1,5- 4.52Hz, 1H), 7.42-7.49 (m, 2H), 7.24-7.33 (m, naphthyridine 2H), 6.96 (dd, J= 4.64, 8.30 Hz, 1H), 4.56 (s, 2H), 4.26 (s, 1H), 3.95-4.02 (m, 2H),3.72-3.86 (m, 2H), 3.08-3.19 (m, 3H), 2.85-2.98 (m, 3H), 2.08 (quin, J =5.98 Hz, 2H), 1.86-1.97 (m, 2H), 1.43- 1.59 (m, 2H) 101 X 563.3 12.87(br s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.53 (d, J = 8.54Hz, 1H), 7.32-7.36 (m, 1H), 7.15-7.26 (m, 4H), 5.27 (brs, 1H), 4.56 (s,2H), 3.99-4.04 (m, 2H), 3.94 (s, 1H), 3.84 (s, 3H), 3.76 (br t, J =11.35 Hz, 2H), 3.02-3.17 (m, 4H), 2.95 (br t, J = 6.47 Hz, 2H),2.64-2.70 (m, 1H), 2.04-2.12 (m, 2H), 1.91-1.99 (m, 1H), 1.81-1.90 (m,1H), 1.56 (br d, J = 12.21 Hz, 1H), 1.22 (br d, J = 12.94 Hz, 1H) 102 L525.2 13.01 (br s, 1H), 7.30-7.36 (m, 1H), 7.13-7.25 (m, 3H), 6.96 (brs, 1H), 6.81-6.82 (m, 1H), 6.78 (br t, J = 7.13 Hz, 1H), 5.26 (br s,1H), 4.55 (br s, 2H), 4.08 (br d, J = 4.93 Hz, 2H), 3.93-3.98 (m, 2H),3.91 (s, 1H), 3.75 (br t, J = 14.78 Hz, 2H), 3.02- 3.17 (m, 3H), 2.65(br d, J = 15.82 Hz, 1H), 2.23 (s, 3H), 1.91-1.99 (m, 1H), 1.85 (br t, J= 10.76Hz, 1H), 1.56 (br d, J = 12.45 Hz, 1H), 1.16-1.23 (m, 1H) 103piperidine 434.2 (CDCl3) 7.32-7.38 (m, 1H), 7.18-7.26 (m, 3H), 4.78 (s,2H), 4.03 (s, 1H), 3.63-3.71 (m, 4H), 3.46-3.57 (m, 2H), 3.04-3.23 (m,3H), 2.68-2.77 (m, 1H), 1.85-2.07 (m, 2H), 1.71-1.80 (m, 5H), 1.67-1.70(m, 2H), 1.39-1.46 (m, 1H). ^(a)Step a ran from 12-72 hr at 95-110° C.Step b deprotection could also be achieved using HCl in acetonitrile orother solvents. ^(b)In Step a, additional catalyst/base was added after16 h, and the reaction was run at 100° C. for an additional 16 h.Compound was racemic.

Compounds Synthesized in a Similar Fashion to Method 8 Example 104:Synthesis of(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

Step a:

{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (98.0 mg, 0.17 mmol, Intermediate K) was dissolved in DCM (2 mL)and TFA (0.5 mL) was added and the reaction mixture was stirred at rtfor 16 h to form intermediate(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate. Then toluene was added and the reaction was concentrated invacuo, then THF was added and the mixture was concentrated again toremove the TFA. The residue was next redissolved in 2 mL THF and 0.5 mLwater then LiOH was added and the reaction mixture was stirred at rt for3 h. The reaction was then concentrated in vacuo and the residue wasredissolved in DMSO with formic acid. The residue was purified on byprep HPLC (5-30% ACN/water/FA) to give(S)-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanolas a yellow solid. LCMS m/z [M+H]⁺=351.1; 1H NMR (500 MHz, DMSO-d₆) ppm:8.28-8.33 (m, 1H), 8.13-8.19 (m, 1H), 7.37-7.43 (m, 1H), 7.18-7.28 (m,4H), 4.59-4.63 (m, 2H), 4.06-4.12 (m, 1H), 3.63-3.74 (m, 2H), 3.06-3.14(m, 2H), 2.75-2.82 (m, 1H), 1.83-1.97 (m, 2H), 1.51-1.60 (m, 2H),1.33-1.41 (m, 2H).

Method 9, Example 105: Synthesis of(3S)-3-amino-1′-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile

Step a:

A mixture of(R)—N-[(1S)-7-cyano-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(153.0 mg, 0.5 mmol, Intermediate BH),1-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine(188.0 mg, 0.5 mmol, Intermediate AA), TEA (640.0 μL, 4.6 mmol) and DMF(4.0 mL) was stirred at 85° C. for 12 hours. The reaction mixture wasconcentrated and quenched with H₂O (30.0 mL). The reaction mixture wasextracted with EtOAc (40.0 mL×3). The combined organic layers werewashed with brine (20.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC (DCM/CH₃OH=10/1) to give(3S)-3-amino-1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile(217.0 mg, 71% yield) as a yellow solid. LCMS m/z (M+H)⁺=666.2.

Step b:

(R)—N-[(3S)-4-cyano-1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(167.0 mg, 0.3 mmol) was added into HCl/MeOH (20.0 mL, 4 M). Thereaction mixture was stirred at 50° C. for 0.5 hour. The combinedreaction mixture was concentrated, and the residue was purified byprep-HPLC (basic condition).(3S)-3-amino-1′-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile(88.8 mg, 61% yield) was obtained as a yellow solid. LCMS m/z(M+H)⁺=478.0; ¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 8.33 (s, 1H),7.91 (d, J=1.6 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.56-7.48 (m, 2H),7.48-7.41 (m, 1H), 6.97 (t, J=4.4 Hz, 1H), 4.20-4.09 (m, 3H), 3.97-3.94(m, 2H), 3.44-3.41 (m, 2H), 3.10 (d, J=12.8 Hz, 1H), 2.94 (t, J=6.4 Hz,2H), 2.86 (d, J=16.4 Hz, 1H), 2.10-2.05 (m, 2H), 1.84-1.43 (m, 4H).

Method 9 Table: Compounds Synthesized Via Method 9, with theCross-Coupling of1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine(Intermediate AA) with Various Amines in Step a

LCMS Example Step a m/z #^(a) Amine (M + H)⁺ ¹H NMR (400 MHz, DMSO-d6) δppm 106 BL 484.1 (CD3OD) 8.26 (s, 1H), 7.87~7.89 (m, 1H), 7.55~7.58 (m,1H), 7.31~7.34 (m, 1H), 7.00~7.04 (m, 1H), 6.64~6.67 (m, 1H), 4.36~4.40(m, 2H), 3.94~3.97 (m, 5H), 3.91 (s, 1H), 3.40~3.51 (m, 2H), 3.04~3.11(m, 3H), 2.77~2.82 (m, 1H), 2.18~2.26 (m, 2H), 1.86~1.98 (m, 2H),1.68~1.73 (m, 1H), 1.51~1.55 (m, 1H). 107 BO 478.1 13.03 (br, 1H), 8.89(s, 3H), 8.44 (s, 1H), 8.15 (d, J = 7.6 Hz, 2H), 7.86-7.80 (m, 3H),7.63-7.58 (m, 1H), 4.50-4.43 (m, 3H), 4.07-4.04 (m, 2H), 3.37-3.24 (m,5H), 3.05 (d, J = 16.8 Hz, 1H), 2.20-2.14 (m, 2H), 1.92-1.75 (m, 2H),1.61- 1.53 (m, 2H). 108 BN 484.1 (CD3OD) 8.37 (s, 1H), 8.23 (d, J = 8.8Hz, 1H), 8.07-8.04 (m, 2H), 7.57 (dd, J = 6.0, 8.4 Hz, 1H), 7.17 (d, J =8.8 Hz, 1H), 4.60-4.55 (m, 2H), 4.46 (br d, J = 14.0 Hz, 1H), 4.12- 4.07(m, 5H), 3.56-3.34 (m, 4H), 3.28-3.26 (m, 2H), 2.33-2.27 (m, 2H),2.01-1.76 (m, 4H) 109 CD 489.1 13.04 (m, 1H), 8.93 (s, 3H), 8.43 (s,1H), 8.16-8.12 (m, 2H), 7.62-7.57 (m, 1H), 7.46-7.43 (m, 1H), 7.25 (m,1H), 4.44-4.42 (m, 3H), 4.06-4.03 (m, 2H), 3.22-3.26 (m, 5H), 3.03-2.98(m, 1H), 2.17-2.14 (m, 2H), 1.86-1.82 (m, 2H), 1.62 (m, 2H). 110 CP457.1 8.37 (s, 1H), 8.03~8.07 (m, 2H), 7.54~7.60 (m, 2H), 4.58~4.62 (m,1H), 4.46~4.50 (m, 1H), 4.23 (s, 1H), 4.08~4.24 (m, 2H), 3.88 (s, 3H),3.48~3.51 (m, 1H), 3.28~3.32 (m, 3H), 3.18~3.23 (m, 1H), 2.96~3.01 (m,1H), 2.29~2.36 (m, 2H), 1.98~2.02 (m, 2H), 1.84~1.89 (m, 2H). 111^(b) I441.2 8.41 (d, J = 1.26 Hz, 1H), 8.24 (s, 1H), 8.12-8.23 (m, 2H), 7.46(br d, J = 7.58 Hz, 1H), 7.27-7.37 (m, 1H), 7.11-7.23 (m, 3H), 7.05 (dd,J = 4.67, 8.21 Hz, 1H), 4.23-4.35 (m, 2H), 3.88 (s, 1H), 3.83 (dd, J =5.31, 6.57 Hz, 2H), 3.17- 3.24 (m, 2H), 3.08 (d, J = 15.92 Hz, 1H), 2.91(t, J = 6.82 Hz, 2H), 2.62-2.70 (m, 1H), 1.94-2.03 (m, 2H), 1.75 (dt, J= 4.17, 12.57 Hz, 1H), 1.58-1.68 (m, 1H), 1.51 (br d, J = 12.13 Hz, 1H),1.14 (br d, J = 13.39 Hz, 1H) 112 CR 489.1 (CD3OD) 8.37 (s, 1H),8.08-8.05 (m, 2H), 7.61-7.58 (m, 1H), 7.28-7.14 (m, 2H), 4.89 (s, 1H),4.58-4.41 (m, 2H), 4.12-4.06 (m, 2H), 3.52-3.41 (m, 2H), 3.31-3.28 (m,4H), 2.34-2.29 (m, 2H), 2.04-1.98 (m, 1H), 1.91-1.85 (m, 2H), 1.72-1.68(m, 1H). 113 CV 468.1 (CD3OD) 9.68 (br s, 1H), 8.17 (s, 1H), 8.06-8.05(m, 1H), 7.66 (d, d, J = 7.2 Hz,, 1H), 7.26-7.24 (m, 1H), 7.17- 7.15 (m,1H), 6.98-6.95 (m, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.45 (d, J = 7.6 Hz,1H), 4.57-4.44 (m, 2H), 4.25 (s, 1H), 4.11-4.09 (m, 2H), 3.30-3.25 (m,2H), 3.09 (t, J = 6.4 Hz, 2H), 2.65 (s, 3H), 2.24-2.19 (m, 3H),1.95-1.77 (m, 2H), 1.47-1.44 (m, 1H). 114^(c) CN 425.1 (CDCl3) 11.02(br, 1H), 7.93-7.96 (m, 1H), 7.59 (s, 1H), 7.49-7.53 (m, 1H), 7.15-7.27(m, 4H), 6.80-6.85 (m, 1H), 4.35 (d, J = 8.4 Hz, 1H), 4.33 (s, 1H), 4.30(d, J = 8.8 Hz, 1H), 4.19 (d, J = 8.8 Hz, 1H), 4.04-4.08 (m, 2H), 3.89(d, J = 8.8 Hz, 1H), 3.38 (d, J = 15.6 Hz, 1H), 3.19 (d, J = 15.6 Hz,1H), 3.06-3.11 (m, 2H), 2.15-2.23 (m, 1H). 115^(c) CO 425.1 (CDCl3)11.11 (br, 1H), 8.02-8.05 (m, 1H), 7.68 (s, 1H), 7.58-7.62 (m, 1H),7.25-7.36 (m, 4H), 6.90-6.94 (m, 1H), 4.44 (d, J = 8.4 Hz, 1H), 4.24 (s,1H), 4.21 (d, J = 8.8 Hz, 1H), 4.10 (d, J = 8.8 Hz, 1H), 3.96-4.00 (m,2H), 3.80 (d, J = 8.8 Hz, 1H), 3.29 (d,J = 15.6 Hz, 1H), 3.10 (d, J =15.6 Hz, 1H), 2.97-3.02 (m, 2H), 2.07-2.14 (m, 1H). 226 EG 481.3(CD3OD)10.37-10.07 (br, 1H), 8.07-8.05 (m, 1H), 8.03 (s, 1H), 7.71-7.68(m, 1H), 7.26-7.24 (d, J = 8.0 Hz, 1H), 7.22-7.18 (t, J = 8.0 Hz, 1H),6.99-6.96 (q, J = 4.0 Hz, 1H), 6.92-6.88 (t, J = 8.0 Hz, 1H), 6.82-6.80(d, J = 8 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 4.12-4.09 (t, J = 6 Hz,2H), 3.89 (s, 1H), 3.11-3.08 (t, J = 6 Hz, 2H), 2.56- 2.47 (m, 2H),2.37-2.32 (m, 1H), 2.24-2.18 (m, 2H), 2.16-2.10 (m, 2H), 2.07-1.97 (m,2H), 1.91-1.87 (m, 1H). 227 EX 479.3 (CDCl3) 10.03-9.99 (br, 1H),8.06-8.05 (m, 1H), 7.99 (s, 1H), 7.70-7.61 (m, 1H), 7.36-7.34 (m, 1H),7.22- 7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.12-7.10 (m, 1H), 6.98-6.95 (q,J = 4.0 Hz, 1H), 4.73 (s, 1H), 4.64 (s, 1H), 4.25 (s, 1H), 4.12-4.09 (t,J = 6.0 Hz, 2H), 3.11-3.08 (t, J = 6.0 Hz, 2H), 2.92-2.88 (d, J = 16 Hz,1H), 2.47-2.44 (d, J = 12 Hz, 1H), 2.34-2.30 (d, J = 16Hz, 1H), 2.24-2.21 (m, 2H), 2.20-2.18 (m, 2H), 2.14-2.08 (m, 2H), 1.98-1.86 (m, 2H),1.68-1.65 (d, J = 12 Hz, 1H). ^(a)Step a was run anywhere from 70-100°C. for 2-12 hr. Hunigs base could also be used in Step a and CsF couldalso be used as an additive. Step b run anywhere from 25-50° C.^(b)Instead of Intermediate AA, (Intermediate CE) was used as thecoupling partner in Step a. No deprotection Step b was required.^(c)After Step a, the intermediate was protected with Boc₂O beforepurification; absolute configuration of the enantiomer was arbitrarilyassigned.

Method 9 Table 2: Compounds Synthesized Via Method 9, with theCross-Coupling of (S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(Intermediate I) with Various Chlorides in Step a

LCMS Example Step a m/z #^(a) Chloride (M + H)⁺ ¹H NMR (400 MHz, CD3OD)δ ppm 178^(b) DA 527.0 7.36-7.39 (m, 2H), 7.20-7.26 (m, 3H), 7.10- 1.15(m, 1H), 6.95-6.97 (m, 1H), 4.01 (s, 1H), 3.54-3.58 (m, 2H), 3.51 (s,3H), 3.12-3.19 (m, 3H), 2.77-2.82 (m, 1H), 1.92-2.06 (m, 2H), 1.63-1.67(m, 1H), 1.46-1.50 (m, 1H). 179^(c,d) 2- 330.9 9.13 (s, 1H), 8.04-8.02(m, 1H), 7.96-7.94 (m, chloroquinoxaline 1H), 7.84-7.80 (m, 1H),7.67-7.62 (m, 1H), 7.57 (CAS# (d, J = 7.2 Hz, 1H), 7.47-7.36 (m, 3H),4.67- 1448- 4.64 (m, 1H), 4.53-4.50 (m, 2H), 3.84-3.74 (m, 87-9) 2H),3.30-3.24 (m, 2H), 2.17-2.00 (m, 3H), 1.83 (d, J = 12.8 Hz, 1H). 180^(d)8-chloro 319.9 (DMSO-d6) 7.97-7.95 (m, 1H), 7.93 (d, J = 4.4 imidazo-Hz, 1H), 7.61-7.59 (m, 1H), 7.38-7.35 (m, 2H), [1,2-a]- 7.28-7.21 (m,3H), 5.28-5.21 (m, 2H), 3.88 (s, pyrazine 1H), 3.38-3.35 (m, 2H), 3.17(d, J = 15.6 Hz, (CAS# 1H), 2.70 (d, J= 15.6 Hz, 1H), 1.91-1.72 (m,69214- 2H), 1.58 (d, J = 12.4 Hz, 1H), 1.18 (d, 33-1) J = 13.2 Hz, 1H).181^(d) DC 335.1 8.26 (s, 1H), 8.20 (s, 1H), 7.41-7.34 (m, 1H),7.30-7.15 (m, 3H), 3.99 (br s, 1H), 3.98 (s, 3H), 3.56 (br d, J = 11.6Hz, 2H), 3.33 (td, J = 1.6, 3.3 Hz, 2H), 3.22 (d, J = 15.8 Hz, 1H),2.90- 2.81 (m, 1H), 1.98-1.75 (m, 2H), 1.70 (br d, J = 13.3 Hz, 1H),1.53 (br d, J = 13.1 Hz, 1H) 182^(d) DD 335.1 8.57 (s, 1H), 8.24 (s,1H), 7.49-7.13 (m, 4H), 4.69-4.56 (m, 2H), 4.20-4.10 (m, 3H), 4.02- 3.95(m, 1H), 3.65-3.47 (m, 2H), 3.33 (td, J = 1.6, 3.3 Hz, 6H), 3.27-3.17(m, 1H), 2.87 (d, J = 15.8 Hz, 1H), 1.99-1.78 (m, 2H), 1.75- 1.66 (m,1H), 1.53 (br d, J = 13.6 Hz, 1H) 183^(e) DH 334.0 7.99 (s, 1H), 7.87(d, J = 5.8 Hz, 1H), 7.43-7.35 (m, 1H), 7.28-7.16 (m, 3H), 6.94 (d, J =5.8 Hz, 1H), 4.81-4.71 (m, 2H), 3.97 (s, 1H), 3.84 (s, 3H), 3.46-3.34(m, 2H), 3.17 (d, J = 15.8 Hz, 1H), 2.82 (d, J = 15.8 Hz, 1H), 2.00-1.81(m, 2H), 1.65-1.55 (m, 1H), 1.52-1.41 (m, 1H) 184^(e) DG 334.0 8.24 (s,1H), 8.02 (d, J = 5.8 Hz, 1H), 7.45-7.33 (m, 2H), 7.29-7.17 (m, 3H),4.23 (s, 3H), 4.09- 3.98 (m, 1H), 3.41 (br dd, J = 3.5, 12.0 Hz, 2H),3.27-3.13 (m, 3H), 2.81 (br d, J = 15.8 Hz, 1H), 2.22-1.87 (m, 2H), 1.72(br s, 1H), 1.54 (br d, J = 12.5 Hz, 1H) 228^(d,f) EJ 351.2 (CDCl3) 8.47(br d, J = 4.4 Hz, 1 H), 7.30- 7.28 (m, 1 H), 7.17-7.13 (m, 3 H), 6.93(s, 1 H), 6.78 (s, 1 H), 4.21-4.13 (m, 2 H), 3.81 (s, 1 H), 3.11-3.01(m, 3 H), 2.75 (d, J = 4.4 Hz, 3 H), 2.61 (br d, J = 15.6 Hz, 1 H), 2.33(s, 3 H), 1.79-1.71 (m, 1 H), 1.65-1.60 (m, 1 H), 1.48 (br d, J = 13.6Hz, 1 H), 1.10-1.05 (m, 1 H) 229^(d,g) DI 359.1 (CD3OD) δ 7.83 (s, 1H),7.73 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.46-7.36 (m, 3H), 4.66-4.51 (m,2H), 4.03-3.88 (m, 1H), 3.75-3.57 (m, 2H), 3.31-3.20 (m, 2H), 2.12-1.86(m, 4H), 1.78- 1.72 (m, 1H), 1.10-1.04 (m, 2H), 0.81-0.77 (m, 2H)230^(d,h) EN 389.1 (CD3OD) 9.38 (s, 1H), 7.82 (s, 1 H), 7.31- 7.29 (m, 1H), 7.20-7.15 (m, 3 H), 4.18-4.11 (m, 2 H), 3.86 (s, 1 H), 3.26-3.16 (m,4 H), 3.09-3.05 (d, J = 15.6 Hz, 1 H), 2.66 (s, 1 H), 1.87-1.80 (m, 1H), 1.77-1.70 (m, 1 H), 1.56- 1.53 (d, J = 13.2 Hz, 1 H), 1.17-1.13 (d,J = 13.2 Hz, 1 H) 231^(d,i) EH 465.2 (CDCl3) 2.89 (d, J = 1.2 Hz, 1H),8.09 (d, J = 1.2 Hz, 1H), 7.73-7.72 (d, J = 4.0 Hz, 1H), 7.36-7.34 (m,1H), 7.21-7.18 (m, 2H), 7.15- 7.13 (m, 1H), 6.10-6.18 (d, J = 8.0 Hz,1H), 4.87 (s, 2H), 4.66 (s, 1H), 4.58 (s, 1H), 4.24 (s, 1H), 2.95-2.91(d, 16 Hz, 1H), 2.47-2.43 (d, 16 Hz, 1H), 2.37-2.33 (d, 16 Hz, 1H),2.21- 2.17 (m, 2H), 2.13-2.04 (m, 2H), 1.94-1.81 (m, 2H), 1.68-1.64 (d,16 Hz, 1H). 232^(d,j) EH 467.2 (CDCl3) 8.30 (d, J = 0.8 Hz, 1H), 8.14(8.30 (d, J = 1.2 Hz, 1H), 7.74-7.72 (d, J = 8.0 Hz, 1H), 7.26-7.25 (m,1H), 7.24-7.20 (t, J = 8.0 Hz, 1H), 6.94-6.90 (t, J = 8.0 Hz, 1H),6.83-6.81 (d, J = 8.0 Hz, 1H), 6.11-6.09 (d, J = 8.0 Hz, 1H), 4.87 (s,2H), 4.78 (s, 1H), 4.68 (s, 1H), 3.92 (s, 1H), 2.56-2.47 (m, 2H),2.33-2.28 (m, 1H), 2.17-2.08 (m, 2H) 2.00-1.99 (m, 2H) 1.91-1.88 (m, 1H)^(a)Step a was run anywhere from 70-100° C. for 2-12 hr. Hunigs basecould also be used in Step a and CsF could also be used as an additive.Step b run anywhere from 25-50° C. ^(b)In Step a, DIPEA was used as thebase and it was heated at 120° C. for 12 h. In Step b, TfOH/TFA was usedfor deprotection which was run at 100° C. for 16 h. ^(c)Step 1 was runat 80° C. for 12 in DMF with Cs₂CO₃ as the base. ^(d)No Step 2deprotection required. ^(e)Intermediate I was free based with sodiumbicarbonate, then 2 drops of NMP was added and the mixture was heated to140° C. for 4 h. No deprotection step was required. ^(f)DIPEA was usedas the base in Step a which was run at 180° C. for 1 h. ^(g)The couplingin Step a was achieved using K₂CO₃ in IPrOh at 120° C. under microwavefor 7 hrs. No Step b was required and the product was purfied usingsilica gel chromoatography (MeOH in DCM from 0-8%) then prep HPLC (HCl)to afford the final product. ^(h)Step a was run in NMP at 180° C. withDIPEA for 2 h. ^(i)Intermediate EX was used as the amine instead ofIntermediate I in Step a. ^(j)Intermediate EG was used as the amineinstead of Intermediate I in Step a, which was achieved using DIPEA asthe base in NMP at 130° C. for 1 h.

Compounds Synthesized in a Similar Fashion to Method 9 Examples 116 and117: Synthesis of(R)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrileand(S)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile

(R)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrileand(S)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrilewas synthesized as described above in Method 9, Example 105, coupling1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile(Intermediate BU) and1-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine(Intermediate AA) in Step a.3-amino-1′-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidine]-7-carbonitrile(100.0 mg) was separated by preparative SFC (column: DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um), Mobile phase: 0.1% NH₃.H₂O IPA (Begin B: 55%, EndB: 55%), Flow rate: 70 mL/min) to afford the product of(R)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile(43.7 mg, R_(t)=5.24 min, the faster eluting isomer) as a yellow solidand(S)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile(31.0 mg, R_(t)=8.44 min, the slower eluting isomer) as a yellow solid.Absolute stereochemistry of the enantiomers was arbitrarily assigned.(R)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile:LCMS m/z (M+H)⁺=478.2; ¹HNMR (400 MHz, Methanol-d₄): 8.23 (s, 1H),7.83-7.89 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.40(t, J=7.8 Hz, 1H), 7.29-7.34 (m, 1H), 6.96-7.02 (m, 1H), 4.63 (s, 1H),4.34-4.48 (m, 2H), 4.03 (s, 1H), 3.90-3.97 (m, 2H), 3.34-3.44 (m, 2H),2.92-3.07 (m, 3H), 2.13-2.25 (m, 2H), 1.78-1.99 (m, 2H), 1.60-1.72 (m,1H), 1.37-1.49 (m, 1H). SFC: e.e. =90.0%.(S)-1-amino-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile:LCMS m/z (M+H)⁺=478.2; ¹HNMR (400 MHz, Methanol-d₄): 8.23 (s, 1H),7.82-7.90 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.40(t, J=7.8 Hz, 1H), 7.28-7.34 (m, 1H), 6.96-7.04 (m, 1H), 4.62 (s, 1H),4.35-4.47 (m, 2H), 4.04 (s, 1H), 3.89-3.97 (m, 2H), 3.34-3.45 (m, 2H),2.94-3.08 (m, 3H), 2.13-2.25 (m, 2H), 1.78-1.99 (m, 2H), 1.61-1.71 (m,1H), 1.38-1.48 (m, 1H). SFC: e.e. =99.5%. Column: Chiralpak AD-3 100×4.6mm I.D., 3 m, Mobile phase: 40% of iso-propanol (0.1% ethanolamine) inCO₂, Flow rate: 2.8 mL/min, Column temperature: 40° C.

Examples 118 & 119: Synthesis of(S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amineand(R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine

Step a:

A mixture of 3H-spiro[1-benzofuran-2,4 (100 mg, 492 μmol, IntermediateAP),1-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine(200 mg, 541 μmol, Intermediate AA) and TEA (148 mg, 1.47 mmol) in DMF(5 mL) was stirred at 80° C. for 12 hours. The reaction mixture wasdiluted with ethyl acetate (50 mL), and washed with H₂O (30 mL×2). Theorganic phase was washed with brine (15 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue, which waspurified by silica gel chromatography (eluent:petroluem ether:ethylacetate=1:1) to give1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-one(250 mg, 95% yield) as a yellow solid. LCMS m/z (M+H)⁺=538.1.

Step b:

A solution of1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-one(230 mg, 427 μmol), AcONH₄ (640 mg, 8.5 mmol) and NaBH₃CN (26.8 mg, 0.42mmol) in EtOH (15 mL) was stirred at 60° C. for 1 hour. The addition ofAcONH₄ (640 mg, 8.5 mmol) and NaBH₃CN (26.8 mg, 0.42 mmol) at 20° C. wasrepeated 2 times. The reaction mixture was stirred at 60° C. for another11 hours. The reaction mixture was poured into H₂O (40 mL) and thenextracted with EtOAc (40 mL×2). The combined organic layers were washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give crude product as a yellowsolid, which was purified by prep-HPLC (NH₃.H₂O) to afford1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine(87.0 mg, 38% yield) as a yellow solid. LCMS m/z (M+H)⁺=539.1.

Step c:

A mixture of1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine(87 mg, 161 umol) in MeOH (5 mL) was added HCl/MeOH (400 uL, 4M). Themixture was stirred at 20° C. for 2 hours. The mixture was concentratedin vacuo to give a residue, which was purified by prep-HPLC (HCl) toafford1′-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride (78.0 mg, 99% yield) as a yellow solid. LCMS m/z(M+H)⁺=455.0.

Step d:

The product ofrac-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-aminehydrochloride (78 mg, 158 μmol) was separated by SFC (Column: DAICELCHIRALPAK AY 250 mm×30 mm, 10 um. Condition: 0.1% NH₃.H₂O ETOH. Begin B:45%. End B: 45%. FlowRate (ml/min): 70) to afford(S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine(30.7 mg, 43% yield, the faster eluting isomer) as a yellow solid and(R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine(39.2 mg, 55% yield, the slower eluting isomer) was obtained as a yellowsolids. Characterization of(S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine:LCMS m/z (M+H)⁺=455.0; ¹HNMR (400 MHz, Methanol-d₄): δ 8.30 (s, 1H),7.89-7.88 (m, 1H), 7.42-7.40 (m, 1H), 7.34-7.33 (m, 1H), 7.23-7.22 (m,1H), 7.15-7.12 (m, 1H), 6.93-6.92 (m, 1H), 6.84-6.82 (m, 1H), 4.51-4.49(m, 2H), 4.20 (s, 1H), 3.97-3.96 (m, 2H), 3.58-3.48 (m, 2H), 3.08-3.01(m, 2H), 2.23-2.20 (m, 2H), 2.02-2.00 (m, 2H), 1.88-1.86 (m, 2H). SFC:e.e.=96.4%, R_(t)=4.82 min. Characterization of(R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine:LCMS m/z (M+H)⁺=455.0; ¹HNMR (400 MHz, MeOD-d₄): δ 8.22 (s, 1H),7.82-7.81 (m, 1H), 7.45-7.39 (m, 2H), 7.38-7.31 (m, 1H), 7.03-6.99 (m,1H), 6.96-6.93 (m, 1H), 6.92-6.89 (m, 1H), 4.85-4.82 (m, 1H), 4.74-4.66(m, 2H), 3.90-3.87 (m, 2H), 3.48-3.42 (m, 2H), 3.01-2.98 (m, 2H),2.14-2.12 (m, 2H), 1.96-1.92 (m, 2H), 1.87-1.82 (m, 2H). SFC:e.e.=94.5%, R_(t)=7.86 min, Column: Chiralpak IC-3 150×4.6 mm I.D., 3um. Mobile phase: 40% of ethanol (0.05% DEA) in CO₂; Flow rate: 2.5mL/min. Column Temperature: 35° C.

Method 10, Example 233: Synthesis of(3S)-1′-[5-(cyclohexylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of tert-butylN-[(3S′)-1′-(5-sulfanylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(65.0 mg, 157 μmol, Intermediate DJ), iodocyclohexane (42.8 mg, 204μmol) and K₂CO₃ (65.0 mg, 471 μmol) in DMF (2.00 mL) was stirred at 70°C. for 12 hours under N₂. The combined reaction mixture was diluted withEtOAc (100 mL), washed with H₂O (20 mL×3) and brine (40 mL×2), thendried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (12 g column, EtOAc inpetroleum ether from 0%˜15%) to give tert-butylN-[(3S)-1′-[5-(cyclohexylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(81.0 mg, combined product) as a yellow solid. LC-MS (ESI⁺) m/z: 517.1(M+Na)⁺.

Step b:

The mixture of tert-butylN-[(3S)-1′-[5-(cyclohexylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(80.0 mg, 161 μmol) in HCl/MeOH (5.00 mL, 4 M) was stirred at 25° C. for0.5 hour. The reaction mixture was then concentrated to give a residue.The residue was dissolved in MeOH (5.00 mL), and the reaction mixturewas adjusted to pH=8-9 with solid Na₂CO₃. The mixture was then filtered,and the filtrate was concentrated to give a residue. The residue waspurified by prep-HPLC (basic condition) to give(3S)-1′-[5-(cyclohexylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(23.6 mg, 37% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 395.1 (M+H)⁺;¹HNMR (400 MHz, CD₃OD): δ 8.17 (d, J=1.3 Hz, 1H), 8.09 (d, J=1.3 Hz,1H), 7.42-7.34 (m, 1H), 7.27-7.17 (7, 3H), 4.21 (td, J=3.5, 13.5 Hz,2H), 3.96 (s, 1H), 3.31-3.19 (d, 3H), 3.16 (d, J=15.8 Hz, 1H), 2.80 (d,J=15.8 Hz, 1H), 2.02-1.73 (3, 6H), 1.70-1.56 (m, 2H), 1.46-1.29 (m, 6H).

Method 10 Table: Compounds Synthesized Via Method 10. With theCross-Coupling of Various Thiols with Various Iodides or Bromides inStep a

Step a LCMS Example Step a Bromide or m/z # Thiol Iodide (M + H)⁺ ¹H NMR(400 MHz, CD₃OD) δ ppm 234^(a) DJ 3-bromo- 383.0 8.19 (s, 1H), 8.11 (s,1H), oxolane 7.41-7.34 (m, 1H), 7.26- (CAS# 7.16 (m, 3H), 4.21 (br d,19311-37-6) J = 13.4 Hz, 2H), 4.12-4.04 (m, 1H), 3.95 (m, 3H), 3.89-3.79 (m, 1H), 3.70 (dd, J = 4.8, 9.1 Hz, 1H), 3.30-3.10 (m, 3H), 2.80(d, J = 15.6 Hz, 1H), 2.35 (br dd, J = 26.9, 13.3 Hz, 1H), 1.98-1.73 (m,3H), 1.66- 1.57 (m, 1H), 1.48-1.39 (m, 1H) 235^(a) DJ 3-bromo- 383.18.21-8.16 (m, 1H), 8.12- oxolane 8.08 (m, 1H), 7.43-7.35 (m, (CAS# 1H),7.26-7.16 (m, 3H), 4.21 19311-37-6) (br d, J = 13.4 Hz, 2H), 4.08 (dd, J= 6.8, 8.7 Hz, 1H), 4.01- 3.90 (m, 3H), 3.88-3.79 (m, 1H), 3.70 (dd, J =4.8, 9.1 Hz, 1H), 3.37 (s, 2H), 3.31-3.10 (m, 3H), 2.80 (br d, J = 15.6Hz, 1H), 2.35 (br dd, J = 7.0, 13.4 Hz, 1H), 1.98-1.69 (m, 3H), 1.60 (brd, J = 13.4 Hz, 1H), 1.43 (br d, J = 13.3 Hz, 1H) 236^(b) DJ bromo 367.08.16 (d, J = 1.3 Hz, 1H), 8.04 cyclobutane (d, J = 1.3 Hz, 1H),7.41-7.36 (m, 1H), 7.26-7.19 (m, 3H), 4.25-4.15 (m, 2H), 4.05- 3.93 (m2H) 3.31-3.12 (m, 3H), 2.82 (d, J = 15.8 Hz, 1H), 2.47-2.35 (m, 2H),2.15- 1.72 (m, 6H), 1.60 (br dd, J = 1.9, 13.4 Hz, 1H), 1.45 (br dd, J =1.5, 13.6 Hz, 1H) 237^(c) FT (bromomethyl) 383.0 8.06 (s, 1H), 7.55-7.47(m, cyclopropane 1H), 7.43-7.29 (m, 3H), 4.72-4.59 (m, 1H), 4.46-4.36(m, 1H), 4.32-4.22 (m, 1H), 3.62-3.40 (m, 2H), 3.25-3.13 (m, 3H),3.09-2.94 (m, 1H), 0 1.96-1.83 (m, 4H), 1.72-1.63 (m, 2H),1.53-1.47 (m,1H), 1.15-1.05 (m, 2H). 238^(d) FA (bromomethyl) 397.1 8.52 (s, 1H),7.93 (s, 1H), cyclopropane 7.50 (m, 1H), 7.42-7.26 (m, 3H), 4.39 (s,1H), 3.71-3.44 (m, 5H), 3.25-3.04 (m, 4H), 2.72 (m, 2H), 2.10-1.84 (m,2H), 1.80-1.51 (m, 2H), 0.95 (m, 1H), 0.62-0.40 (m, 2H), 0.29-0.07 (m,2H) 239^(d) FF (bromomethyl) 387.0 8.25 (s, 1H), 8.02 (m, 1H),cyclopropane 7.92 (m, 1H), 7.01 (m, 1H), 6.93-6.79 (m, 1H), 6.67 (m,1H), 4.28-4.12 (m, 2H), 4.02 (s, 1H), 3.29-3.14 (m, 2H), 2.75 (m, 2H),1.89-1.73 (m, 2H), 1.71-1.52 (m, 2H), 0.94- 0.72 (m, 1H), 0.45-0.22 (m,2H), 0.10-0.09 (m, 2H) 240^(d) FR (bromomethyl) 387.0 8.21 (s, 1H), 8.01(m, 1H), cyclopropane 7.90 (m, 1H), 7.27 (m, 1H), 6.62-6.40 (m, 2H),4.34- 4.14 (m, 2H), 4.03 (m, 1H), 3.28-3.11 (m, 2H), 2.74 (m, 2H),1.92-1.75 (m, 2H), 1.73- 1.52 (m, 2H), 0.82 (s, 1H), 0.45-0.22 (m, 2H),0.10- 0.15 (m, 2H) ^(a)The racemic compound from Step b was separated byChiral-SFC (DAICEL CHIRALCEL OD-H(250 mm*30 mm, 5 um). Mobile phase: 30%of EtOH (0.1% NH3•H2O) in CO2. Flow rate: 70 mL/min). Absoluteconfiguration was arbitrailv assigned. ^(b)Step a ran at 80° C. for 12h. ^(c)TEA in DMF at rt for 1 h was utilized in Step a. Step b usedTFA/TfOH at 100° C. for 1 hr for the deprotection. ^(d)TEA used as thebase in Step a. EtAOc was used as a solvent in Step b.

Compounds Synthesized in a Similar Fashion to Method 10 Example 241:Synthesis of(S)-1′-(5-(cyclopropylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of tert-butylN-[(3S)-1′-(5-sulfanylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(130.0 mg, 315 μmol, Intermediate DJ), cyclopropylboronic acid (134.0mg, 1.57 mmol), Cu(OAc)₂ (114.0 mg, 630 μmol) and TEA (261 μL, 1.88mmol) in DCM (10 mL) was stirred at 40° C. for 12 h under O₂. Thereaction mixture was then filtered and the filtrate was concentrated togive a residue. The residue was purified by flash silica gelchromatography (4 g column, EtOAc in petroleum ether from 0%˜20%) togive tert-butylN-[(3S)-1′-[5-(cyclopropylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(42.0 mg, 30% yield) as a white solid. LC-MS (ESI⁺) m/z: 453.1 (M+H)⁺.

Step b:

A mixture of tert-butylN-[(3S)-1′-[5-(cyclopropylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(40.0 mg, 88.3 μmol) in HCl/MeOH (5.00 mL, 4 M) was stirred at 25° C.for 0.5 hour. The mixture was concentrated to give a residue and theresidue was dissolved in MeOH (3 mL). The mixture was adjusted topH=9-10 with solid Na₂CO₃. The mixture was then filtered and thefiltrate was purified by prep-HPLC (basic condition) to afford(S)-1′-(5-(cyclopropylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(13.1 mg, 42% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 352.9 (M+H)⁺;¹H NMR (400 MHz, CD₃OD): δ 8.20 (d, J=1.5 Hz, 1H), 8.13 (d, J=1.5 Hz,1H), 7.43-7.35 (m, 1H), 7.27-7.17 (m, 3H), 4.19 (m, 2H), 3.97 (s, 1H),3.30-3.12 (m, 3H), 2.82 (d, J=15.8 Hz, 1H), 2.38-2.28 (m, 1H), 1.97-1.72(m, 2H), 1.61 (m, 1H), 1.45 (m, 1H), 1.09-1.00 (m, 2H), 0.72-0.63 (m,2H).

Example 242: Synthesis(S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2,3-dichlorophenyl)thio)-3-methylpyrimidin-4(3H)-one

Step a:

Tert-butyl (S)-tert-butyl(1′-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(75.0 mg, 139 μmol, Intermediate DQ), XantPhos (16.0 mg, 27.8 μmol),DIPEA (46.1 μL, 278 μmol), Pd₂(dba)₃ (12.7 mg, 13.9 t mol) and2,3-dichlorobenzenethiol (29.7 mg, 166 μmol, CAS #17231-95-7) wereplaced into dioxane (4.0 mL). The reaction mixture was evacuated andrefilled 3 times using N₂. The reaction mixture was stirred at 100° C.for 12 hours. The reaction mixture was then concentrated and purified byflash silica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:60) to afford (S)-tert-butyl(1′-(5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(90.0 mg, 110% crude yield) as a brown oil. LC-MS (ESI+) m/z: 587.1(M+H)⁺.

Step b:

A mixture of (S)-tert-butyl(1′-(5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(88 mg, 149 μmol) in HCl/EtOAc (6.00 mL, 4 M) was stirred at 15° C. for1 hour. The reaction mixture was concentrated under reduce pressure. Theresidue was dissolved with MeOH (5.00 mL) and adjusted to pH=7-8 withsolid Na₂CO₃. The mixture was then filtered and the filtrate waspurified by prep-HPLC (HCOOH) to afford(S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2,3-dichlorophenyl)thio)-3-methylpyrimidin-4(3H)-one(34.0 mg, 43% yield) as a white solid. LC-MS (ESI+) m/z: 487.0 (M+H)⁺;¹HNMR (400 MHz, Methonol-d₄) δ=8.53 (s, 1H), 8.15 (s, 1H), 7.52 (m, 1H),7.45-7.29 (m, 4H), 7.15 (m, 1H), 6.89 (m, 1H), 4.40 (s, 1H), 3.90-3.62(m, 2H), 3.56 (s, 3H), 3.39-3.34 (m, 1H), 3.32-3.27 (m, 1H), 3.24-3.06(m, 2H), 2.15-1.86 (m, 2H), 1.85-1.56 (m, 2H).

Example 243: Synthesis of{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}methanol

Step a:

To a solution of (S)-methyl6-bromo-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazine-2-carboxylate(3 g, 5.79 mmol, Intermediate DN) and 2,3-dichloropyridine-4-thiol (1.14g, 6.36 mmol, CAS #1803809-56-4) in dioxane (30 mL) were added Pd₂(dba)₃(529 mg, 579 umol), XantPhos (665 mg, 1.15 mmol) and DIPEA (3 mL, 17.3mmol). The reaction mixture was evacuated and refilled 3 times using N₂and the reaction mixture was stirred at 120° C. for 12 hours. Thereaction mixture was then concentrated under reduced pressure to givethe residue, which was purified by column chromatography (petroleumether:ethyl acetate=100:0 to 100:20) to afford methyl (S)-methyl3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2,3-dichloropyridin-4-yl)thio)pyrazine-2-carboxylate(1.70 g, 48% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 616.1 (M+H)⁺.

Step b:

To a solution of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazine-2-carboxylate(500 mg, 810 μmol) in THE (15 mL) was added DIBAL-H (806 μL, 1.21 mmol,1.5M in toluene) at −78° C. under N₂. The solution was stirred foranother 2 hours at the same temperature. Then the reaction was quenchedby a solution of 10% aqueous AcOH (50 mL) at −78° C. and extracted withEtOAc (50 mL×3). The combined organic layers were adjusted to pH to 8-9with saturated aqueous of NaHCO₃ and separated. The organic layer waswashed with brine (100 mL), dried over anhydrous N_(a2)SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (petroleum ether:ethyl acetate=100:0 to 100:30) toafford tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]-3-formylpyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(260 mg, 55% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 588.0 (M+H)⁺.

Step c:

Tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]-3-(hydroxymethyl)pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120 mg, 203 μmol) was added into HCl/MeOH (10 mL, 2 M). The mixture wasstirred at 25° C. for 2 h. The mixture was then adjusted to pH=7-8 withsolid Na₂CO₃. The mixture was filtered and the filtrate was concentratedto give a residue. The residue was dissolved in MeOH (4 mL). Then themixture was concentrated and was purified by prep-HPLC (FA) to afford{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}methanolformate (19.2 mg, 18% yield) as a white solid. LC-MS (ESI⁺) m z 488.0(M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄) δ 8.43 (s, 1H), 8.50-8.37 (m, 1H),8.26 (s, 1H), 7.91 (d, J=5.3 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.31-7.16(m, 3H), 6.73 (d, J=5.3 Hz, 1H), 4.64-4.58 (m, 2H), 4.56-4.45 (m, 2H),4.23 (s, 1H), 3.99-3.71 (m, 2H), 3.30-3.22 (m, 2H), 3.15-2.88 (m, 2H),2.01-1.75 (m, 2H), 1.70-1.44 (m, 2H).

Example 244: Synthesis of(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((cyclopropylmethyl)thio)pyrazin-2-yl)methanol

Step a:

A mixture of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-sulfanylpyrazine-2-carboxylate(179.0 mg, 380.0 μmol, Intermediate FB), (bromomethyl)cyclopropane(153.0 mg, 1.1 mmol) and TEA (260˜10 μL, 1.9 mmol) in DMF (5.0 mL) wasstirred at 70° C. for 12 hours under N₂. The combined reaction mixturewas diluted with EtOAc (100 mL), washed with H₂O (20 mL×3), brine (40mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash silica gel chromatography (12 g column,EtOAc in petroleum ether from 0%˜15%) to give methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(cyclopropylmethyl)sulfanyl]pyrazine-2-carboxylate(230.0 mg, combined product) as a yellow solid. LC-MS (ESI⁺) m/z: 525.1(M+H)⁺.

Step b:

To a solution of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(cyclopropylmethyl)sulfanyl]pyrazine-2-carboxylate(230.0 mg, 438.0 μmol) in THE (15.0 mL) was added DIBAL-H (873.0 μL, 1.3mmol, 1.5 M in toluene) at −78° C. under N₂. The solution was warmed to20° C. and stirred for 4 hours. The reaction was quenched with asolution of 10% aqueous AcOH (20 mL) at −78° C. and extracted with EtOAc(30 mL×3). The combined organic layer was adjusted pH to 8˜9 withsaturated aqueous of NaHCO₃ and separated. The organic layer was washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (petroleum ether:ethyl acetate=100:0 to 100:100) toafford tert-butylN-[(3S)-1′-{5-[(cyclopropylmethyl)sulfanyl]-3-(hydroxymethyl)pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 23% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 519.1 (M+Na)⁺.

Step c:

A mixture of tert-butylN-[(3S)-1′-{5-[(cyclopropylmethyl)sulfanyl]-3-(hydroxymethyl)pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(49.0 mg, 98.6 μmol) was dissolved in EtOAc (0.5 mL). HCl/EtOAc (0.5 mL,4 M) was then added and the reaction was stirred at 25° C. for 1 hour.The reaction mixture was then diluted with MeCN (5 mL) and adjusted topH=7-8 with solid Na₂CO₃. MeOH (2.00 mL) was added and the mixture wasfiltered, and the filtrate was concentrated to give a residue. Theresidue was purified by prep-HPLC (HCOOH) to give(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((cyclopropylmethyl)thio)pyrazin-2-yl)methanolformate salt (2.1 mg, 5% yield) as a white solid. LC-MS (ESI+) m/z:397.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.57 (br d, J=2.3 Hz, 1H), 8.10(s, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.37-7.24 (m, 3H), 4.70 (s, 2H), 4.25(s, 1H), 3.56-3.40 (m, 2H), 3.20-3.09 (m, 5H), 3.04-2.94 (m, 1H),2.04-1.90 (m, 2H), 1.64 (m, 2H), 1.18-1.06 (m, 1H), 0.64-0.51 (m, 2H),0.35-0.25 (m, 2H).

Compounds Synthesized Via Further Methodology Example 120: Synthesis of{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}methanol

Step a:

A solution of tert-butyl(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate(1.30 g, 3.19 mmol, Intermediate H) in TFA/DCM (3.0 mL/15.0 mL) wasstirred at 20° C. for 0.5 hour. The reaction mixture was concentratedunder reduced pressure. The residue was diluted with MeOH (20.0 mL),adjusted pH=9 with solid Na₂CO₃, filtered and concentrated to give(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(2.00 g, crude, 50% purity) as a yellow solid. LCMS m/z [M+H]⁺=307.1.

Step b:

A solution of methyl 3-chloropyrazine-2-carboxylate (200.0 mg, 1.15mmol, CAS #27825-21-4),(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(772.0 mg, 1.26 mmol, 50% purity) and CsF (522.0 mg, 3.44 mmol) in DMSO(15.0 mL) was stirred at 60° C. for 1 hour. The reaction mixture waspoured into H₂O (60.0 mL) and extracted with EtOAc (60.0 mL×2). Thecombined organic layers were washed with brine (40.0 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive an orange residue. The residue was purified by flash silica gelchromatography (12 g column, ethyl acetate in petroleum ether from 0% to65%) to give methyl3-[(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(450.0 mg, 89% yield) as a yellow oil. LCMS m/z [M+H]⁺=443.1.

Step c:

A solution of methyl3-[(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(450.0 mg, 1.01 mmol) in HCl/MeOH (20.0 mL, 4 M) was stirred at 20° C.for 1 hour. The reaction mixture was concentrated under reduced pressureto give the product of methyl3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylatehydrochloride (400.0 mg, quant. crude yield) as an orange solid. LCMSm/z [M+H]⁺=339.1.

Step d:

To a solution of methyl3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylatehydrochloride (350.0 mg, 933.0 μmol) in DCM (20.0 mL) was added DIBAL-H(3.73 mL, 3.73 mmol, 1 M in toluene) at 0° C. under N₂. The reactionmixture was stirred at 0° C. for 1 hour. The reaction mixture wasquenched with 10% AcOH. The reaction mixture was concentrated underreduced pressure to give a residue, which was purified by prep-HPLC(NH₃.H₂O) to give{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}methanol(58.2 mg, 20% yield) as a white solid. LCMS m/z [M+H]⁺=311.1; ¹HNMR (400MHz, CD₃OD): 8.12-8.18 (m, 2H), 7.39-7.42 (m, 1H), 7.21-7.24 (m, 3H),4.72 (s, 2H), 4.03 (s, 1H), 3.53-3.57 (m, 2H), 3.11-3.19 (m, 3H),2.79-2.84 (m, 1H), 1.91-2.05 (m, 2H), 1.61-1.66 (m, 1H), 1.48-1.52 (m,1H).

Examples 121 & 122: Synthesis of(R)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methylpyrazin-2-yl)methanoland(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methylpyrazin-2-yl)methanol

Step a:

A mixture of methyl 3-chloro-5-methylpyrazine-2-carboxylate (250 mg, 1.3mmol, Intermediate AK), 1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminedihydrochloride (473 mg, 1.7 mmol, Intermediate E) and CsF (1.0 g, 6.6mmol) in DMSO (15 mL) was stirred at 80° C. for 12 hours. The reactionmixture was used directly in the next step without further purification.LCMS m/z (M+H)⁺=352.9.

Step b:

A mixture of methyl3-{3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}-5-methylpyrazine-2-carboxylate(450 mg, 1.3 mmol, in DMSO from Step a) and (Boc)₂O (548 mg, 2.5 mmol)in aqueous NaOH (2N, 30 mL) was stirred at 20° C. for 12 hours. Thereaction mixture was extracted with ethyl acetate (50 mL×2). The organicphases were washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified silica gel chromatography (ethyl acetate in petroleum ether=0%to 50%) to afford methyl3-(3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methylpyrazine-2-carboxylate(490 mg, 85% yield) as a yellow solid. LCMS m/z (M+H)⁺=453.2.

Step c:

To a mixture of LiAlH₄ (100 mg, 2.6 mmol) in anhydrous THE (10 mL) at 0°C. was added the solution of methyl3-(3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methylpyrazine-2-carboxylate(400 mg, 883 μmol) in THE (10 mL), and the resulting mixture was stirredat this temperature for 2 hours. The reaction mixture was quenched with15% NaOH (0.1 mL) and filtered. The filtrate was concentrated in vacuoto give a residue, which was purified by prep-HPLC (NH₃.H₂O) to affordtert-butylN-{1′-[3-(hydroxymethyl)-6-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(80 mg, 21% yield) as a brown solid. LCMS m/z (M+H)⁺=425.1.

Step d:

The compound of tert-butylN-{1′-[3-(hydroxymethyl)-6-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(80 mg, 188 μmol) was separated by preparative SFC (column: DAICELCHTRALPAK AY-H (250 mm×30 mm, 5 um), Mobile phase: 0.1% NH₃.H₂O EtOH(Begin B: 45%, End B: 45%), Flow rate: 70 mL/min) to afford the productof tert-butyl(R)-(1′-(3-(hydroxymethyl)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(35 mg, 44% yield, R_(t)=1.79 min, the faster eluting isomer) as a whitesolid and tert-butyl(S)-(1′-(3-(hydroxymethyl)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(37 mg, 46% yield, R_(t)=4.81 min, the slower eluting isomer) as a whitesolid. Absolute stereochemistry of the enantiomers was arbitrarilyassigned. LCMS m/z (M+H)⁺=425.1. for both enantiomers, SFC: e.e.=100%for both enantiomers, Chiralpak AY 150×4.6 mm I.D., 3 um; Mobile phase:40% of ethanol (0.05% DEA) in CO₂; Flow rate: 2.5 mL/min; Temperature:35° C.

Step e:

A mixture of tert-butylN-[(3R)-1′-[3-(hydroxymethyl)-6-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(33 mg, 77.7 μmol) in HCl/MeOH (4 M, 2 mL) was stirred at 15° C. for 2hours. The reaction mixture was concentrated in vacuo to afford theproduct of(R)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methylpyrazin-2-yl)methanolhydrochloride (23.3 mg, 90% yield) as a yellow solid. LCMS m/z(M+H)⁺=325.0; ¹HNMR (400 MHz, Methanol-d₄): δ 7.99 (s, 1H), 7.55 (d,J=7.2 Hz, 1H), 7.45-7.34 (m, 3H), 4.93 (s, 2H), 4.47 (s, 1H), 4.01-3.98(m, 1H), 3.88-3.84 (m, 1H), 3.49-3.38 (m, 2H), 3.21 (d, J=4.8 Hz, 2H),2.63 (s, 3H), 2.10-2.03 (m, 1H), 1.97-1.90 (m, 1H), 1.83-1.80 (m, 1H),1.69-1.65 (m, 1H).

Step f:

A mixture of tert-butylN-[(3S)-1′-[3-(hydroxymethyl)-6-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(37 mg, 87.1 μmol) in HCl/MeOH (4 M, 2 mL) was stirred at 15° C. for 2hours. The reaction mixture was concentrated in vacuo to afford theproduct of(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methylpyrazin-2-yl)methanolhydrochloride (28.7 mg, 91% yield) as a yellow solid. LCMS m/z(M+H)⁺=324.9; ¹HNMR (400 MHz, Methanol-d₄): δ 8.00 (s, 1H), 7.55 (d,J=7.6 Hz, 1H), 7.45-7.34 (m, 3H), 4.92 (s, 2H), 4.46 (s, 1H), 4.01-3.97(m, 1H), 3.86-3.83 (m, 1H), 3.48-3.37 (m, 2H), 3.21 (s, 2H), 2.62 (s,3H), 2.09-2.02 (m, 1H), 1.96-1.89 (m, 1H), 1.83-1.80 (m, 1H), 1.69-1.65(m, 1H).

Example 123: Synthesis of{5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}methanol

Step a:

The mixture of methyl 3,5-dichloropyrazine-2-carboxylate (1.0 g, 4.83mmol), (3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminedihydrochloride (1.65 g, 4.83 mmol, Intermediate I) and CsF (3.66 g,24.1 mmol) in DMF (15 mL) was stirred at 70° C. for 2 hours. Boc₂O (1.57g, 7.24 mmol) and TEA (1 mL) were added to the mixture and the mixturewas stirred at 20° C. for 1 hour. The mixture was diluted with H₂O (50mL), extracted with EtOAc (50 mL×2). The organic layer was washed withbrine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure and the residue was purified by columnchromatography (petroleum ether/ethyl acetate=1:0˜5:1) to afford methyl5-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-chloropyrazine-2-carboxylate(1.58 g, 69% yield) as a yellow solid and methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-chloropyrazine-2-carboxylate(320 mg, 14% yield) as a yellow solid. LCMS m/z (M+H)⁺=473.1 for bothisomers.

Step b:

The mixture of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-chloropyrazine-2-carboxylate(280 mg, 592 μmol), diphenylmethanimine (128 mg, 710 μmol), Cs₂CO₃ (577mg, 1.77 mmol), Pd₂(dba)₃ (27.1 mg, 29.6 μmol) and BINAP (36.8 mg, 59.2μmol) in PhMe (10 mL) was evacuated and refilled 3 times using N₂. Themixture was stirred at 100° C. for 12 hours. The reaction wasconcentrated under reduced pressure. The residue was diluted with H₂O(20 mL), and extracted with EtOAc (20 mL×2). The organic layer waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=1:0˜3:1) to afford themixture methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-[(diphenylmethylidene)amino]pyrazine-2-carboxylate(LCMS m/z (M+H)⁺=618.2) and methyl5-amino-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(LCMS m/z (M+H)⁺=454.2) (260 mg, with the 73% purity as a mixture ofboth isomers).

Step c:

The mixture of methyl3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-[(diphenylmethylidene)amino]pyrazine-2-carboxylateand methyl5-amino-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(240 mg, 73% purity) in HCl/MeOH (4M, 10 mL) was stirred at 25° C. for 2hours. The mixture was concentrated under reduced pressure and theresidue was diluted with MeOH. The mixture was adjusted to pH=8 by solidNa₂CO₃. The mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography(DCM/MeOH=1:0˜10:1) to methyl5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(70 mg) as a yellow oil. LCMS m/z (M+H)⁺=354.1

Step d:

To a solution of methyl5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazine-2-carboxylate(130 mg, 367 μmol) in THE (10 mL) was added LiAlH₄ (139 mg, 3.66 mmol).The mixture was stirred at 25° C. for 1 hour. Then the mixture wasdiluted with THE (30 mL). 15% NaOH (0.14 mL) was added and the mixturewas filtered. The filtrate was concentrated under reduced pressure andthe residue was purified by prep-HPLC (NH₃.H₂O) to afford{5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}methanol(20.2 mg, 17% yield) as a white solid. LCMS m/z (M+H)⁺=326.2; ¹HNMR (400MHz, Methanol d₄): δ 7.47 (s, 1H), 7.41-7.38 (m, 1H), 7.23-7.20 (m, 3H),4.57 (s, 2H), 3.99 (s, 1H), 3.57-3.53 (m, 2H), 3.14-3.08 (m, 3H),2.81-2.76 (m, 1H), 1.97-1.89 (m, 2H), 1.60-1.56 (m, 1H), 1.47-1.43 (m,1H).

Example 124: Synthesis of(S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

To a mixture of tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(500 mg, 0.8 mmol, Intermediate J) and1,2,3,4-tetrahydro-1,5-naphthyridine (136 mg, 1.0 mmol) in toluene (5.0mL) were added XantPhos-Pd-G4 (60.4 mg, 79.2 μmol) and Cs₂CO₃ (514 mg,1.6 mmol). The reaction mixture was purged with N₂ for 3 min and stirredat 100° C. for 12 hours. The reaction mixture was concentrated underreduced pressure to give the residue which was purified by columnchromatography (petroleum ether:ethyl acetate=100:0 to 100:80). Theproduct tert-butylN-[(3S)-1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(460 mg, 91% yield) was obtained as a yellow solid. LCMS m/z[M+H]⁺=637.3.

Step b:

To a solution of tert-butylN-[(3S)-1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(430 mg, 0.7 mmol) in MeCN (2.5 mL) and AcOH (2.5 mL) was added NBS (132mg, 0.7 mmol). The reaction was stirred at 25° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure to give theresidue which was purified by column chromatography (petroleumether:ethyl acetate=100:0 to 100:70). The product of tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(400 mg, 83% yield) was obtained as a yellow solid. LCMS m/z[M+H]⁺=715.1/717.1.

Step c:

To a mixture of tert-butyl((1S)-1′-(5-bromo-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(400 mg, 0.6 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborinane (76.9 mg,0.6 mmol) in dioxane (5.0 mL) and H₂O (0.5 mL) were added Pd(dppf)Cl₂(40.8 mg, 55.8 μmol) and K₂CO₃ (153 mg, 1.1 mmol). The reaction mixturewas purged with N₂ for 3 min and stirred at 100° C. for 12 hours underN₂. The reaction mixture was concentrated under reduced pressure to givethe residue which was purified by column chromatography (petroleumether:ethyl acetate=100:0 to 100:70). The product of tert-butyl((1S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(240 mg, 66% yield) was obtained as a yellow solid. ¹HNMR (400 MHz,CDCl3): 8.06-8.07 (m, 1H), 7.82-7.84 (m, 1H), 7.31-7.37 (m, 1H),7.27-7.26 (m, 3H), 6.99-7.03 (m, 1H), 5.78-5.81 (m, 1H), 5.06-5.10 (m,1H), 4.70-4.73 (m, 1H), 4.11-4.18 (m, 3H), 3.84-4.00 (m, 2H), 3.74-3.79(m, 1H), 3.22-3.29 (m, 1H), 3.05-3.11 (m, 3H), 2.81-2.85 (m, 1H),2.61-2.64 (m, 1H), 2.14-2.25 (m, 4H), 1.90-1.97 (m, 2H), 1.70-1.85 (m,4H), 1.52 (s, 9H).

Step d:

A solution of tert-butylN-[(3S)-1′-[5-methyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(230 mg, 0.4 mmol) in HCl/MeOH (10.0 mL, 4M) was stirred at 25° C. for12 hours. The reaction mixture was concentrated under reduced pressure.The residue was dissolved in MeOH (8.0 mL) and the solution was purifiedby reverse phase prep-HPLC (HCl). The product of(S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (145 mg, 82% yield) was obtained as a yellow solid. LCMSm/z [M+H]⁺=467.2; ¹HNMR (400 MHz, Methanol-d₄): 8.04-8.06 (d, J=5.6,1H), 7.93-7.96 (d, J=8.4, 1H), 7.54-7.58 (m, 2H), 7.40-7.46 (m, 2H),7.34-7.38 (m, 1H), 4.48 (s, 1H), 4.08-4.11 (m, 2H), 3.77-3.81 (m, 1H),3.67-3.71 (m, 1H), 3.24-3.30 (m, 4H), 3.21 (s, 2H), 2.64 (s, 3H),2.30-2.37 (m, 2H), 2.07-2.14 (m, 1H), 1.95-2.02 (m, 1H), 1.84-1.87 (m,1H), 1.70-1.73 (m, 1H). SFC: e.e. =98.4%.

Example 125: Synthesis of6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-N,5-dimethyl-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide

Step a:

A mixture of tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250 mg, 396 μmol, Intermediate J), methanamine hydrochloride (534 mg,7.9 mmol), Pd₂(dppf)Cl₂ (28.9 mg, 39.6 μmol) and TEA (1.1 mL, 7.9 mmol)in MeOH (10 mL) was stirred at 80° C. for 12 hours under CO atmosphere(50 psi). The reaction mixture was concentrated in vacuo to give aresidue, which was dissolved in ethyl acetate (50 mL), then washed withH₂O (25 mL×2). The organic phase was washed with brine (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give aresidue, which was purified by silica gel chromatography (ethyl acetatein petroleum ether=0% to 95%) to afford tert-butylN-[(3S)-1′-[3-(methylcarbamoyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(210 mg, 95% yield) as a brown solid. LCMS m/z [M+H]⁺=562.1.

Step b:

A mixture of tert-butylN-[(3S)-1′-[3-(methylcarbamoyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(210 mg, 373 μmol), NBS (132 mg, 746 μmol) in MeCN (10 mL) and AcOH (1mL) was stirred at 25° C. for 12 hours. The reaction mixture wasconcentrated in vacuo to give a residue, which was dissolved in ethylacetate (20 mL), then washed with sat.NaHCO₃ (15 mL×2). The organicphase was washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (ethyl acetate in petroleumether=0% to 80%) to afford tert-butylN-[(3S)-1′-[5-bromo-3-(methylcarbamoyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100 mg, 42% yield) as a yellow oil. LCMS m/z [M+H]⁺=640.1.

Step c:

A mixture of tert-butylN-[(3S)-1′-[5-bromo-3-(methylcarbamoyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100 mg, 156 μmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (194 mg, 1.6mmol), Pd(dppf)Cl₂ (11.4 mg, 15.6 μmol) and K₂CO₃ (43.0 mg, 312 μmol) in1,4-dioxane (10 mL)/H₂O (1 mL) was stirred at 90° C. for 12 hours underN₂ atmosphere. The reaction mixture was concentrated in vacuo to give aresidue, which was purified by silica gel chromatography (ethyl acetateas eluent) to afford tert-butylN-[(3S)-1′-[5-methyl-3-(methylcarbamoyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 56% yield) as a brown oil. LCMS m/z [M+H]⁺=576.2.

Step d:

A mixture of tert-butylN-[(3S)-1′-[5-methyl-3-(methylcarbamoyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50 mg, 86.8 μmol) in HCl/MeOH (4M, 2 mL) was stirred at 25° C. for 1hour. The mixture was concentrated under reduced pressure to give aresidue, which was purified by prep-HPLC (HCl) to afford6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-N,5-dimethyl-1H-pyrazolo[3,4-b]pyrazine-3-carboxamidehydrochloride (15.5 mg, 42% yield) as a yellow solid. LCMS m/z[M+H]⁺=392.1; ¹HNMR (400 MHz, Methanol-d₄): δ 7.55 (d, J=7.2 Hz, 1H),7.45-7.34 (m, 3H), 4.49 (s, 1H), 3.80-3.68 (m, 2H), 3.31-3.21 (m, 4H),3.07 (s, 3H), 2.74 (s, 3H), 2.14-1.96 (m, 2H), 1.86-1.83 (m, 1H),1.73-1.70 (m, 1H).

Example 126: Synthesis of(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)oxyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

The mixture of tert-butylN-[(3S)-1′-{3-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(2.6 g, 67% purity, 3.12 mmol, Intermediate BE), 2,3,4-trichloropyridine(682 mg, 3.74 mmol) and Cs₂CO₃ (3.05 g, 9.36 mmol) in DMF (30 mL) wasstirred at 70° C. for 12 hours. Then the mixture was diluted with H₂O(50 mL), and extracted with EtOAc (50 mL×2). The organic layer waswashed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=1:0˜3:1) to affordtert-butylN-[(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(1.58 g, 72% yield) as a yellow oil. LCMS m/z [M+H]⁺=702.1.

Step b:

The mixture of tert-butylN-[(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100 mg, 142 μmol) in TFA (5 mL) and TfOH (0.5 mL) was stirred at 20° C.for 10 hours. The combined mixture was concentrated under reducedpressure and the residue was diluted with MeOH. The mixture was adjustedto pH=8 by solid Na₂CO₃. The mixture was filtered and the filtrate waspurified by prep-HPLC (NH₃.H₂O) to afford(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(30 mg, 44% yield) as a white solid. LCMS m/z [M+Na]⁺=504.0. ¹HNMR (400MHz, DMSO-d₆+Methanol_d₄): δ 8.37 (s, 1H), 8.22-8.20 (d, J=6.4 Hz, 1H),7.41-7.39 (m, 1H), 7.28-7.22 (m, 3H), 7.13-7.11 (d, J=6.4 Hz, 1H),4.44-4.43 (m, 2H), 3.99 (s, 1H), 3.42-3.32 (m, 2H), 3.23-3.19 (m, 1H),2.87-2.82 (m, 1H), 1.93-1.83 (m, 2H), 1.68-1.64 (m, 1H), 1.49-1.45 (m,1H).

Example 127: Synthesis of(3S)-1′-{3-[(3-chloro-2-methylpyridin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

The mixture of tert-butylN-[(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100 mg, 142 μmol, synthesized via Step a of Example 126),trimethyl-1,3,5,2,4,6-trioxatriborinane (35.6 mg, 284 μmol), Pd(dppf)Cl₂(10.3 mg, 14.2 μmol) and K₃PO₄.3H₂O (113 mg, 425 μmol) in H₂O (0.5 ml)and dioxane (5 mL) was evacuated and refilled 3 times using N₂. Themixture was stirred at 100° C. for 12 hours. The reaction mixture wasthen concentrated under reduced pressure and the residue was purified bycolumn chromatography (petroleum ether/ethyl acetate=1:0˜2:1) to affordtert-butylN-[(3S)-1′-{3-[(3-chloro-2-methylpyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(170 mg, combined product with another identical reaction) as a yellowsolid. LCMS m/z [M+H]⁺=682.2.

Step b:

The mixture of tert-butylN-[(3S)-1′-{3-[(3-chloro-2-methylpyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(150 mg, 219 μmol) in TFA (5 mL) and TfOH (0.5 mL) was stirred at 90° C.for 0.5 hour. The mixture was then concentrated under reduced pressureand the residue was diluted with MeOH. The mixture was adjusted to pH=8by solid Na₂CO₃. The mixture was filtered and the filtrate was purifiedby prep-HPLC (NH₃.H₂O) to afford(3S)-1′-{3-[(3-chloro-2-methylpyridin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(23.7 mg, 23% yield) as a white solid. LCMS m/z [M+H]⁺=462.1; ¹HNMR (400MHz, Methanol_d₄): δ 8.29 (s, 1H), 8.21-8.19 (d, J=5.6 Hz, 1H),7.39-7.36 (m, 1H), 7.26-7.20 (m, 3H), 6.96-6.94 (d, J=5.6 Hz, 1H),4.44-4.39 (m, 2H), 3.97 (s, 1H), 3.39-3.35 (m, 2H), 3.21-3.16 (m, 1H),2.85-2.80 (m, 1H), 2.67 (s, 3H), 1.91-1.80 (m, 2H), 1.65-1.61 (m, 1H),1.48-1.44 (m, 1H).

Example 128: Synthesis of(S)-4-((6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)oxy)-3-chloro-1-methylpyridin-2(1H)-one

Step a:

The mixture of tert-butylN-[(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(450 mg, 499 μmol, synthesized via Step a of Example 126), Pd₂(dba)₃ (46mg, 50 μmol), t-BuXPhos (43 mg, 100 μmol) and KOH (83 mg, 1.49 mmol) indioxane (5 mL) and H₂O (5 mL) was stirred at 100° C. for 10 hours underN₂. The reaction mixture was then extracted with EtOAc (10 mL×2). Thecombined organic layers were washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (petroleum ether/ethylacetate=1:0˜1:2) to afford tert-butylN-[(3S)-1′-{3-[(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(150 mg, 44% yield) as a yellow solid. LCMS m/z [M+H]⁺=684.1.

Step b:

To a mixture of tert-butylN-[(3S)-1′-{3-[(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(140 mg, 204 μmol) and Cs₂CO₃ (199 mg, 612 μmol) in DMF (5 mL) was addedMel (70.1 μL, 1.12 mmol). The mixture was stirred at 25° C. for 0.5hour. The combined mixture was diluted with H₂O (20 mL), and extractedwith EtOAc (20 mL×2). The combined organic layers were washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(petroleum ether/ethyl acetate=1:1˜1:2) to afford tert-butylN-[(3S)-1′-{3-[(3-chloro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(140 mg) as a yellow oil. LCMS m/z [M+H]⁺=698.2.

Step c:

The mixture of tert-butylN-[(3S)-1′-{3-[(3-chloro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(130 mg, 186 umol) in TFA (3 mL) and TfOH (0.3 mL) was stirred at 90° C.for 0.5 hour. The mixture was concentrated under reduced pressure andthe residue was diluted with MeOH, then adjusted with Na₂CO₃ to pH=8.The mixture was purified by prep-HPLC (NH₃.H₂O) to afford(S)-4-((6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)oxy)-3-chloro-1-methylpyridin-2(1H)-one(24.2 mg, 27% yield) as a white solid. LCMS m/z [M+H]⁺=477.9; ¹HNMR (400MHz, DMSO-d₆+Methanol_d₄): δ 8.38 (s, 1H), 7.66-7.63 (d, J=7.6 Hz, 1H),7.42-7.23 (m, 4H), 6.21-6.18 (d, J=7.6 Hz, 1H), 4.48-4.43 (m, 2H), 3.98(s, 1H), 3.63 (s, 3H), 3.37-333 (m, 2H), 3.25-3.20 (m, 1H), 2.87-2.82(m, 1H), 1.90-1.33 (m, 4H).

Example 129: Synthesis of(S)-1′-(5-((6-amino-2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of(R)-2-methyl-N-[(3S)-1′-[5-(sodiosulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]propane-2-sulfinamide(550 mg, 877 μmol, Intermediate BR), tert-butylN-(4,5,6-trichloropyridin-2-yl)carbamate (866 mg, 877 μmol, IntermediateBQ) and Cs₂CO₃ (570 mg, 1.8 mmol) in DMF (30 mL) was stirred at 70° C.for 12 hours. The reaction mixture was diluted with ethyl acetate (60mL), washed with H₂O (40 mL×2). The organic phase was washed with brine(15 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give a residue, which was purified by silica gel chromatography(ethyl acetate in petroleum ether=0% to 70%) to afford the product oftert-butylN-[5,6-dichloro-4-({5-[(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)pyridin-2-yl]carbamate(330 mg, 56% yield) as a yellow solid. LCMS m/z [M+H]⁺=677.1.

Step b:

A mixture of tert-butylN-[5,6-dichloro-4-({5-[(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)pyridin-2-yl]carbamate(300 mg, 442 μmol) in HCl/MeOH (4M, 10 mL) was stirred at 20° C. for 0.5hour. The mixture was concentrated under reduced pressure to give thecrude product, which was triturated with MeOH (3 mL) and filtered toafford(S)-1′-(5-((6-amino-2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (167.5 mg, 74% yield) as a yellow solid. LCMS m/z[M+H]⁺=472.9; ¹HNMR (400 MHz, Methanol-d₄): δ 8.43 (d, J=1.6 Hz, 1H),8.34 (d, J=1.2 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.44-7.35 (m, 3H), 5.93(s, 1H), 4.52-4.34 (m, 3H), 3.48-3.36 (m, 2H), 3.24 (s, 2H), 1.97-1.67(m, 4H).

Example 130: Synthesis of(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of(R)-2-methyl-N-[(3S)-1′-[5-(sodiosulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]propane-2-sulfinamide(1.2 g, purity: 70%, Intermediate BR), 2,3,4-trichloropyridine (547 mg,2.1 mmol) and Cs₂CO₃ (1.2 g, 3.8 mmol) in DMF (50 mL) was stirred at 70°C. for 2 hours. The mixture was diluted with ethyl acetate (110 mL), andwashed with H₂O (100 mL×2). The combined organic phases were washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give a residue, which was purified by silica gel chromatography(ethyl acetate in petroleum ether=0% to 80%) to afford(R)—N-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(900 mg, 84% yield) as a white solid. LCMS m/z [M+H]⁺=562.0/564.0.

Step b:

A mixture of(R)—N-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(80 mg, 142 μmol) in HCl/MeOH (4M, 2 mL) was stirred at 20° C. for 0.5hours. The mixture was concentrated under reduced pressure to give thecrude product. The residue was triturated with MeOH (2 mL), filtered andconcentrated in vacuo to afford(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (32.1 mg, 46% yield) as a yellow solid. LCMS m/z[M+H]⁺=457.9; ¹HNMR (400 MHz, Methanol-d₄): δ 8.44 (s, 1H), 8.36 (s,1H), 8.03 (d, J=5.2 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.46-7.35 (m, 3H),6.73 (d, J=5.2 Hz, 1H), 4.53-4.36 (m, 3H), 3.49-3.37 (m, 2H), 3.24 (s,2H), 1.96-1.67 (m, 4H).

Example 131: Synthesis of4-({5-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)-3-chloro-1,2-dihydropyridin-2-one

Step a:

A mixture of(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (700 mg, 1.4 mmol, Example 130), (Boc)₂O (609 mg, 2.8mmol) and TEA (1.0 mL, 7.1 mmol) in DCM (20 mL) was stirred at 20° C.for 3 hours. The mixture was diluted with H₂O (30 mL), and extractedwith dichloromethane (30 mL×3). The combined organic phases were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (ethyl acetate in petroleum ether=0% to 50%)to afford tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(720 mg, 91% yield) as a white solid. LCMS m/z [M+H]⁺=558.0/560.0.

Step b:

A mixture of tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(700 mg, 1.3 mmol), KOH (210 mg, 3.8 mmol), t-Bu-XPhos (106 mg, 250μmol) and Pd₂(dba)₃ (114 mg, 125 μmol) in dioxane (10 mL) and H₂O (10mL) was stirred at 100° C. for 12 hours under N₂ atmosphere. Thereaction mixture was diluted with H₂O (40 mL), and extracted with ethylacetate (40 mL×3). The organic phases were washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by silica gel chromatography (ethylacetate as eluent) to afford tert-butylN-[(3S)-1′-{5-[(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(420 mg, 62% yield) as a yellow solid. LCMS m/z [M+H]⁺=540.1.

Step c:

A mixture of tert-butylN-[(3S)-1′-{5-[(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(110 mg, 203 μmol) in HCl/MeOH (4M, 2 mL) was stirred at 20° C. for 1hour. The mixture was concentrated under reduced pressure andlyophilized to afford4-({5-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)-3-chloro-1,2-dihydropyridin-2-onehydrochloride (87.4 mg, 90% yield) as a yellow solid. LCMS m/z[M+H]⁺=439.9; ¹HNMR (400 MHz, DMSO-d₆): δ 8.58 (s, 3H), 8.53 (s, 1H),8.36 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.38-7.24 (m, 5H), 5.52 (d, J=6.8Hz, 1H), 4.42-4.29 (m, 3H), 3.30-3.22 (m, 3H), 3.01 (d, J=16.0 Hz, 1H),1.87-1.75 (m, 2H), 1.60-1.54 (m, 2H).

Example 132: Synthesis of4-({5-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)-3-chloro-1-methyl-1,2-dihydropyridin-2-one

Step a:

To a mixture of tert-butylN-[(3S)-1′-{5-[(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250 mg, 462 μmol, synthesized via Steps a-b of Example 131) and Cs₂CO₃(449 mg, 1.4 mmol) in DMF (20 mL) was added Mel (745 μL, 11.9 mmol), theresulting mixture was stirred at 20° C. for 0.5 hours. The reactionmixture was diluted with ethyl acetate (50 mL), and washed with H₂O (40mL×2). The organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by silica gel chromatography (ethyl acetate aseluent) to afford tert-butylN-[(3S)-1′-{5-[(3-chloro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250 mg, 98% yield) as a yellow solid. LCMS m/z [M+H]⁺=554.0.

Step b:

A mixture of tert-butylN-[(3S)-1′-{5-[(3-chloro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(240 mg, 433 μmol) in HCl/MeOH (4M, 10 mL) was stirred at 20° C. for 0.5hours. The mixture was concentrated under reduced pressure to give aresidue, which was lyophilized to afford4-({5-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrazin-2-yl}sulfanyl)-3-chloro-1-methyl-1,2-dihydropyridin-2-onehydrochloride (161 mg, 76% yield) as a yellow solid. LCMS m/z[M+H]⁺=453.9; ¹HNMR (400 MHz, DMSO-d₆): δ 8.62 (s, 3H), 8.53 (s, 1H),8.35 (s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.38-7.28(m, 3H), 5.59 (d, J=7.2 Hz, 1H), 4.42-4.29 (m, 3H), 3.44 (s, 3H),3.30-3.22 (m, 3H), 3.01 (d, J=16.0 Hz, 1H), 1.88-1.77 (m, 2H), 1.61-1.54(m, 2H).

Example 133: Synthesis of(3S)-1′-{5-[(2-amino-3-chloropyridin-4-yl)oxy]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To a mixture of 2-bromo-5-[(2,3-dichloropyridin-4-yl)oxy]pyrazine (500mg, 1.6 mmol, Intermediate BS) and(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(570 mg, 1.9 mmol, synthesized via Step a of Example 120) in toluene(5.0 mL) were added RuPhos-Pd-G4 (131 mg, 0.2 mmol), RuPhos (144 mg, 0.3mmol) and Cs₂CO₃ (1.0 g, 3.1 mmol). The reaction mixture was purged withN₂ for 3 min and stirred at 100° C. for 12 hours under N₂. The reactionmixture was concentrated under reduced pressure. The residue was dilutedwith water (100.0 mL) and extracted ethyl acetate (200.0 mL×2). Thecombined organic layers were washed with H₂O (100.0 mL) and brine (100.0mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (petroleum ether ethyl acetate=100:0 to 100:60) to give(R)—N-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)oxy]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(220 mg, 26% yield) as a light yellow solid. LCMS m/z [M+H]⁺=546.0.

Step b:

To a mixture of(R)—N—((S)-1′-(5-((2,3-dichloropyridin-4-yl)oxy)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(220 mg, 0.4 mmol) and diphenylmethanimine (134 μL, 0.8 mmol) in toluene(5.0 mL) were added Pd₂(dba)₃ (36.7 mg, 40.2 μmol), BINAP (50.0 mg, 80.4μmol) and Cs₂CO₃ (261 mg, 0.8 mmol). The reaction mixture was purgedwith N₂ for 3 min and stirred at 100° C. for 12 hours under N₂. Thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (petroleumether:ethyl acetate=100:0 to 100:70) to give(R)—N—((S)-1′-(5-((3-chloro-2-((diphenylmethylene)amino)pyridin-4-yl)oxy)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(170 mg, 61% yield) as a yellow solid. LCMS m/z [M+H]⁺=691.1.

Step c:

A solution of(R)—N-[(3S)-1′-[5-({3-chloro-2-[(diphenylmethylidene)amino]pyridin-4-yl}oxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(150 mg, 0.2 mmol) in HCl/MeOH (5.0 mL, 0.5 M) was stirred at 25° C. for1 hour. The reaction mixture was purified by prep-HPLC (HCl) to give(3S)-1′-{5-[(2-amino-3-chloropyridin-4-yl)oxy]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (85.0 mg, 86% yield) as a yellow solid. LCMS m/z[M+H]⁺=423.1; ¹HNMR (400 MHz, Methanol-d₄): 8.16-8.17 (m, 1H), 8.05 (s,1H), 7.86-7.88 (d, J=7.2, 1H), 7.53-7.55 (d, J=7.6, 1H), 7.40-7.45 (m,2H), 7.34-7.38 (m, 1H), 7.65-7.67 (d, J=7.2, 1H), 4.44 (s, 1H),4.35-4.39 (m, 1H), 4.21-4.25 (m, 1H), 3.37-3.41 (m, 1H), 3.30-3.32 (m,1H), 3.17-3.26 (m, 2H), 1.77-1.99 (m, 3H), 1.64-1.67 (m, 1H).

Example 134: Synthesis of(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)oxy]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A solution of(R)—N-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)oxy]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(90 mg, 0.2 mmol, synthesized via Step a of Example 133) in HCl/MeOH(5.0 mL, 0.5M) was stirred at 25° C. for 0.5 hours. On completion, thereaction mixture was adjusted to pH=8 with solid K₂CO₃. The reaction wasfiltered and the filtrate was purified by prep-HPLC (NH₃.H₂O) to give(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)oxy]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(30 mg, 41% yield) as a white solid. LCMS m/z [M+H]⁺=442.0; ¹HNMR (400MHz, CDCl₃): 8.08-8.10 (d, J=5.6, 1H), 7.99 (s, 1H), 7.70 (s, 1H),7.25-7.27 (m, 1H), 7.14-7.17 (m, 3H), 6.77-6.79 (d, J=5.6, 1H),4.01-4.09 (m, 2H), 3.93 (s, 1H), 3.09-3.19 (m, 2H), 3.00-3.04 (m, 1H),2.65-2.69 (m, 1H), 1.79-1.86 (m, 1H), 1.69-1.76 (m, 1H), 1.55-1.59 (m,1H), 1.31-1.35 (m, 1H).

Example 135: Synthesis of4-({6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}oxy)-3-chloro-1,2-dihydropyridin-2-one

Step a:

The mixture of tert-butylN-[(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250 mg, 355 μmol, synthesized via Step a of Example 126), Pd₂(dba)₃ (33mg, 36 μmol), t-BuXPhos (30 mg, 71 μmol) and KOH (59 mg, 1.1 mmol) indioxane (5 mL) and H₂O (5 mL) was stirred at 100° C. for 10 hours underN₂. The reaction mixture was then extracted with EtOAc (10 mL×2). Theorganic layer was washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (petroleum ether/ethylacetate=1:0˜1:2) to afford tert-butylN-[(3S)-1′-{3-[(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(180 mg, 74% yield) as a yellow solid. LCMS m/z [M+H]⁺=684.1.

Step b:

The mixture of tert-butylN-[(3S)-1′-{3-[(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(160 mg, 233 μmol) in TFA (3 mL) and TfOH (0.5 mL) was stirred at 90° C.for 0.5 hour. The mixture was concentrated under reduced pressure andthe residue was diluted with MeOH, adjusted pH=8 with Na₂CO₃. Themixture was purified by prep-HPLC (NH₃.H₂O) to afford4-({6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}oxy)-3-chloro-1,2-dihydropyridin-2-one(24.2 mg, 22% yield) as a white solid. LCMS m/z [M+H]⁺=464.2; ¹HNMR (400MHz, DMSO-d₆): δ 8.43 (s, 1H), 7.37-7.29 (m, 2H), 7.19-7.16 (m, 3H),5.98-5.96 (m, 1H), 4.38-4.30 (m, 2H), 3.84 (s, 1H), 3.18-3.08 (m, 3H),2.67-2.62 (m, 1H), 1.83-1.53 (m, 3H), 1.15-1.11 (m, 1H).

Examples 136 and 137: Synthesis ofrel-(R)-1′-(3-((2-amino-3-chloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineandrel-(S)-1′-(3-((2-amino-3-chloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

The mixture of tert-butylN-[(tert-butoxy)carbonyl]-N-(1′-{3-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(500 mg, 80% purity, 609 μmol, Intermediate BV), 2,3,4-trichloropyridine(133 mg, 730 μmol) and Cs₂CO₃ (593 mg, 1.82 mmol) in DMF (5 mL) wasstirred at 100° C. for 24 hours. The mixture was diluted with H₂O (20mL), and extracted with EtOAc (20 mL×2). The combined organic layerswere washed with brine (20 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to afford the residue. Theresidue was purified by column chromatography (petroleum ether/ethylacetate=1:0˜3:1) to afford tert-butylN-(1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(160 mg, 37% yield) as a yellow solid. LCMS m/z [M+H]⁺=702.2.

Step b:

The mixture of tert-butylN-(1′-{3-[(2,3-dichloropyridin-4-yl)oxy]-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate(140 mg, 199 μmol), Pd₂(dba)₃ (18.2 mg, 19.9 μmol), diphenyl imine (43.1mg, 238 μmol), Cs₂CO₃ (194 mg, 597 μmol) and BINAP (24.7 mg, 39.8 μmol)in PhMe (10 mL) was evacuated and refilled for 3 times using N₂. Thenthe reaction mixture was stirred at 100° C. for 12 hours. The mixturewas concentrated under reduced pressure to afford the residue, which waspurified by column chromatography (petroleum ether/ethylacetate=1:0˜3:1) to afford tert-butylN-{1′-[3-({3-chloro-2-[(diphenylmethylidene)amino]pyridin-4-yl}oxy)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(120 mg, 71% yield) as a yellow oil. LCMS m/z [M+H]⁺=847.2.

Step c:

The mixture of tert-butylN-{1′-[3-({3-chloro-2-[(diphenylmethylidene)amino]pyridin-4-yl}oxy)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl}carbamate(110 mg, 129 μmol) in TFA (3 mL) and TfOH (0.3 mL) was stirred at 20° C.for 5 hours. The mixture was concentrated under reduced pressure toafford a residue, which was purified by column chromatography(DCM/MeOH=1:0˜10:1) to afford1′-{3-[(2-amino-3-chloropyridin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(35.0 mg, 59% yield) as a yellow oil. LCMS m/z [M+H]⁺=463.1.

Step d:

1′-{3-[(2-amino-3-chloropyridin-4-yl)oxy]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(30 mg, 64.8 μmol) was separated by Chiral SFC (Column: DAICEL CHIRALCELOJ-H (250 mm×30 mm, 5 um). Condition: 0.1% NH₃.H₂O MeOH. Begin B 40%.End B 40%. Flow rate: 50 mL/min). The product ofrel-(R)-1′-(3-((2-amino-3-chloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(10 mg, 33% yield, the faster eluting isomer) was obtained as a whitesolid and the product ofrel-(S)-1′-(3-((2-amino-3-chloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(10 mg, 33% yield, the slower eluting isomer) was obtained as a whitesolid. Absolute stereochemistry of the enantiomers was arbitrarilyassigned. Characterization ofrel-(R)-1′-(3-((2-amino-3-chloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z [M+H]⁺=463.1; ¹HNMR (400 MHz, Methanol_d₄): δ 8.32 (s, 1H),7.73-7.75 (d, J=6 Hz, 1H), 7.40-7.42 (m, 1H), 7.21-7.29 (m, 3H),6.27-6.29 (d, J=6 Hz, 1H), 4.42-4.47 (m, 2H), 4.06 (s, 1H), 3.36-3.44(m, 2H), 3.19-3.23 (m, 1H), 2.90-2.94 (m, 1H), 1.80-1.93 (m, 2H),1.64-1.67 (m, 1H), 1.52-1.55 (m, 1H). SFC: e.e. =99.5%, R_(t)=4.992 min.Characterization ofrel-(S)-1′-(3-((2-amino-3-chloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS m/z [M+H]⁺=463.1; ¹HNMR (400 MHz, Methanol_d₄): δ 8.32 (s, 1H),7.73-7.75 (d, J=6 Hz, 1H), 7.38-7.40 (m, 1H), 7.21-7.28 (m, 3H),6.27-6.29 (d, J=6 Hz, 1H), 4.42-4.47 (m, 2H), 4.00 (s, 1H), 3.36-3.44(m, 2H), 3.18-3.22 (m, 1H), 2.84-2.88 (m, 1H), 1.79-1.94 (m, 2H),1.63-1.67 (m, 1H), 1.47-1.51 (m, 1H). SFC: e.e. =96.6%, R_(t)=5.265 min.Column: Chiralcel OJ-H 150*4.6 mm I.D., 5 um. Mobile phase: A: CO₂ B:methanol (0.05% DEA). Gradient: hold 5% for 0.5 min, then from 5% to 40%of B in 3.5 min and hold 40% for 2.5 min, then 5% of B for 1.5 min. Flowrate: 3 mL/min Column temp: 40° C.

Example 138: Synthesis of(S)—N₄-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridine-2,4-diamine

Step a:

A mixture of tert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(350.0 mg, 555.0 μmol, from Intermediate J), 2,3-dichloropyridin-4-amine(135.0 mg, 832.0 μmol, CAS #184416-83-9), XantPhos-Pd-G4 (47.6 mg, 55.4μmol) and Cs₂CO₃ (270.0 mg, 832.0 μmol) in PhMe (10 mL) was stirred at100° C. for 12 hours. The reaction mixture was concentrated and purifiedby silica gel column (EtOAc in petroleum ether=0˜30%) to give tert-butylN-[(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)amino]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 54% yield) as a yellow solid. LCMS m/z [M+H]⁺=665.1.

Step b:

A mixture of tert-butylN-[(3S)-1′-{3-[(2,3-dichloropyridin-4-yl)amino]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(180.0 mg, 270.0 μmol), Ph₂C═NH (73.4 mg, 405.0 μmol), Cs₂CO₃ (177.0 mg,540.0 μmol), Pd₂(dba)₃ (24.7 mg, 27.0 μmol) and BINAP (33.6 mg, 54.0μmol) in PhMe (10 mL) was stirred at 100° C. for 12 hours under N₂. Thereaction mixture was concentrated and purified by silica gel column(EtOAc in petroleum ether=0˜30%) to give tert-butylN-[(3S)-1′-[3-({3-chloro-2-[(diphenylmethylidene)amino]pyridin-4-yl}amino)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 55% yield) as a yellow solid. LCMS m/z (M+H−Ph₂C)⁺=646.2.

Step c:

A solution of tert-butylN-[(3S)-1′-[3-({3-chloro-2-[(diphenylmethylidene)amino]pyridin-4-yl}amino)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 148.0 μmol) in 4M HCl/MeOH (10.0 mL) was stirred at 25° C.for 1 hour. The reaction mixture was concentrated and dissolved in MeOH(5 mL) and purified by prep-HPLC (HCl) to give(S)—N₄-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridine-2,4-diamine(23.0 mg) as a yellow solid.(S)—N₄-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridine-2,4-diamine(e.e. =70%) was separated by chiral SFC (Column: DAICEL CHIRALPAK AS-H250 mm*30 mm, 5 um; Mobile phase: A: CO₂, B: Ethanol (0.1% NH₃.H₂O);Gradient: keep 50% of B; Flow rate: 50 mL/min; Column temp: 35° C.).Some impurity was introduced, so the product was re-purified byprep-HPLC (HCl) again to give(S)—N₄-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridine-2,4-diaminedihydrochloride (8.0 mg) as a yellow solid. LCMS m/z [M+H]⁺=462.1. ¹HNMR(400 MHz, CD₃OD): 8.40 (s, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.2Hz, 1H), 7.35-7.45 (m, 3H), 7.17 (d, J=7.6 Hz, 1H), 4.40-4.60 (m, 3H),3.40-3.55 (m, 2H), 3.24 (s, 2H), 1.65-2.00 (m, 4H); SFC: e.e. =98.8%,R_(t)=3.501 min. Column: AS-3 100×4.6 mm I.D., 3 um; Mobile phase: A:CO₂ B: ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.8 mL/min;Column temp.: 35° C.

Example 139: Synthesis of(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

2,5-dibromopyrazine (1.02 g, 4.31 mmol),(3S)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminedihydrochloride (1.15 g, 3.92 mmol, Intermediate T) and TEA (2.69 mL,19.5 mmol) were added in DMF (0.23M, 17 mL). The mixture was stirred at85° C. for 12 h. EtOAc and brine were added to the reaction mixture, andthe solution was extracted with EtOAc (3×). The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (0-20% MeOH in DCM with 0.1% NH₄₀H) to give(S)-1′-(5-bromopyrazin-2-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(1.36 g, 84% yield). LCMS m/z [M]⁺=377.3.

Step b:

(3S)-1′-(5-bromopyrazin-2-yl)-7-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(1.36 g, 3.60 mmol), 3-chloro-4-(sodiosulfanyl)pyridin-2-amine (657 mg,3.60 mmol, Intermediate AC), and Pd-Xantphos-G4 (346 mg, 0.3600 mmol)were placed in a microwave vial and evacuated and backfilled withnitrogen. DIPEA (3.13 mL, 18.0 mmol) and dioxane (15 mL) were added andthe reaction was heated to 110° C. in a microwave for 16 h. The reactionwas filtered through celite and rinsed with EtOAc and concentrated. Theresidue was purified by column chromatography (100 g column, 0-20% MeOHin DCM with 0.1% NH₄₀H). The material was repurifed reverse phase HPLC(5-40% ACN in water with 0.1% formic acid) to give(S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(173 mg, 10% yield). LCMS m/z [M+H]⁺=457.3; ¹H NMR (500 MHz, DMSO-d6) δppm 8.46 (d, J=0.78 Hz, 1H), 8.27-8.30 (m, 1H), 8.23-8.27 (m, 1H), 7.65(d, J=5.19 Hz, 1H), 7.24-7.30 (m, 1H), 7.19-7.24 (m, 1H), 7.00-7.07 (m,1H), 5.75-5.89 (m, 1H), 4.22-4.35 (m, 2H), 4.03 (s, 1H), 3.21-3.31 (m,2H), 3.14 (d, J=16.08 Hz, 1H), 2.77 (d, J=15.82 Hz, 1H), 1.74-1.81 (m,1H), 1.65-1.73 (m, 1 H), 1.52-1.59 (m, 1H), 1.26-1.32 (m, 1H).

Example 140: Synthesis of(S)-1′-(5-(difluoromethyl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A solution of tert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.50 g, 2.37 mmol, Intermediate J),1,2,3,4-tetrahydro-1,5-naphthyridine (381.0 mg, 2.84 mmol),XantPhos-Pd-G4 (227.0 mg, 237.0 umol) and Cs₂CO₃ (1.54 g, 4.74 mmol) inPhMe (50.0 mL) was stirred at 100° C. for 12 hours under N₂. Thereaction mixture was poured into H₂O (200.0 mL) and extracted with EtOAc(200.0 mL×2). The combined organic layers were washed with brine (200.0mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a brown residue. The residue was purified byflash silica gel chromatography (40 g column, ethyl acetate in petroleumether from 0% to 65%) to give tert-butyl((1S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.20 g, 80% yield) as a yellow oil. LCMS m/z [M+H]⁺=637.2.

Step b:

To a solution of tert-butyl((1S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(1.20 g, 1.88 mmol) in MeCN/AcOH (30.0 mL/30.0 mL) was added NBS (334.0mg, 1.88 mmol) in portions at 20° C. The reaction mixture was stirred at20° C. for 1 hour. The reaction mixture was concentrated under reducedpressure. The residue was triturated with saturated NaHCO₃ (150.0 mL)and extracted with EtOAc (150.0 mL×2). The combined organic layers werewashed with brine (200.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (40 g column, ethyl acetatein petroleum ether from 0% to 60%) to give tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(1.25 g, 93% yield) as a yellow oil. LCMS m/z [M+H]⁺=715.1/717.1.

Step c:

A solution of tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(1.25 g, 1.74 mmol), potassium vinyltrifluoroborate (466.0 mg, 3.48mmol), Pd(dppf)Cl₂ (254.0 mg, 348.0 umol) and K₃PO₄.3H₂O (2.60 g, 5.22mmol) in i-PrOH/H₂O (20.0 mL/2.0 mL) was stirred at 100° C. for 12 hourunder N₂. The reaction mixture was poured into H₂O (200.0 mL) andextracted with EtOAc (200.0 mL×2). The combined organic layers werewashed with brine (150.0 mL), dried over anhydrous Na₂SO₄, filtered andfiltrate concentrated under reduced pressure to give a brown residue.The residue was purified by flash silica gel chromatography (40 gcolumn, ethyl acetate in petroleum ether from 0% to 75%) to givetert-butylN-[(3S)-1′-[5-ethenyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(1.00 g, 87% yield) as a yellow solid. LCMS m/z [M+H]⁺=663.2.

Step d:

To a solution of tert-butylN-[(3S)-1′-[5-ethenyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(1.00 g, 1.50 mmol) in acetone/H₂O (21.0 mL/7.0 mL) was addedK₂OsO₄.2H₂O (55.2 mg, 150.0 umol) and NaIO₄ (963.0 mg, 4.50 mmol) at 20°C. The reaction mixture was stirred at 20° C. for 1 hour. The reactionmixture was filtered and filtrate concentrated under reduced pressure togive a residue. The residue was purified by flash silica gelchromatography (40 g column, ethyl acetate in petroleum ether from 0% to70%) to give tert-butylN-[(3S)-1′-[5-formyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(520.0 mg, 52% yield) as a yellow solid. LCMS m/z [M+H]⁺=665.2.

Step e:

To a solution of tert-butylN-[(3S)-1′-[5-formyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 376.0 μmol) in DCM (5.0 mL) was added DAST (303.0 mg, 1.88mmol) at 0° C. under N₂. The reaction mixture was stirred at 0° C. for 1hour. The reaction mixture was quenched with H₂O (30.0 mL) and extractedwith DCM (20.0 mL×2). The combined organic layers were washed with brine(20.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a brown residue. The residue was purified byflash silica gel chromatography (12 g column, ethyl acetate in petroleumether from 0% to 70%) to give tert-butylN-[(3S)-1′-[5-(difluoromethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 19% yield) as an orange oil. LCMS m/z [M+H]⁺=687.2.

Step f:

A solution of tert-butylN-[(3S)-1′-[5-(difluoromethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 72.8 μmol) in HCl/MeOH (3.0 mL, 4 M) was stirred at 20° C. for2 hours. The reaction mixture was concentrated under reduced pressure.The residue was diluted with MeOH (3.0 mL) and purified by prep-HPLC(HCl). The product of(S)-1′-(5-(difluoromethyl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (4.30 mg, 11% yield) was obtained as a yellow solid. LCMSm/z [M+H]⁺=503.1; ¹HNMR (400 MHz, CD₃OD): 8.31-8.34 (m, 1H), 8.10-8.12(m, 1H), 7.61-7.64 (m, 1H), 7.54-7.57 (m, 1H), 7.36-7.44 (m, 3H),6.86-7.12 (m, 1H), 4.48 (s, 1H), 4.21-4.25 (m, 2H), 3.71-3.86 (m, 2H),3.36-3.43 (m, 2H), 3.29-3.31 (m, 2H), 3.21 (s, 2H), 2.31-2.37 (m, 2H),2.11-2.13 (m, 1H), 2.01-2.10 (m, 1H), 1.83-1.87 (m, 1H), 1.69-1.73 (m,1H).

Examples 141 and Example 142: Synthesis of(R)-1-(6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)ethan-1-oland(S)-1-(6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)ethan-1-ol

Step a:

To a solution of tert-butylN-[(3S)-1′-[5-formyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(260.0 mg, 391.0 μmol, synthesized via Step a-d of Example 140) in THF(10.0 mL) was added MeMgBr (390.0 uL, 1.17 mmol, 3 M in THF) at 20° C.under N₂. The reaction mixture was stirred at 20° C. for 3 hours. Thereaction mixture was quenched with H₂O (30.0 mL) and extracted withEtOAc (50.0 mL×2). The combined organic layers were washed with brine(50.0 mL), dried over anhydrous Na₂SO₄, filtered and filtrateconcentrated under reduced pressure to give a brown residue. The residuewas purified by flash silica gel chromatography (12 g column, ethylacetate in petroleum ether from 0% to 85%) to give tert-butylN-[(3S)-1′-[5-(1-hydroxyethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 75% yield) as a yellow solid. LCMS m/z [M+H]⁺=681.2.

Step b:

A solution of tert-butylN-[(3S)-1′-[5-(1-hydroxyethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 293.0 μmol) in TFA/DCM (5.0 mL/5.0 mL) was stirred at 30° C.for 12 hours. The reaction mixture was concentrated under reducedpressure. The residue was diluted with MeOH (5.0 mL), adjusted to pH=9with solid Na₂CO₃ and purified by prep-HPLC (NH₃.H₂O).1-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}ethan-1-ol(40.0 mg, 28% yield) was obtained as a yellow solid. LCMS m/z[M+H]⁺=497.1.

Step c:

1-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}ethan-1-ol(40.0 mg, 80.5 μmol) was separated by preparative SFC (column: DAICELCHIRALPAK AD (250 mm×30 mm, 10 um), Mobile phase: 0.1% NH₃.H₂O ETOH(Begin B: 40%, End B: 40%), Flow rate: 70 ML/MIN) to afford(R)-1-(6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)ethan-1-ol(9.6 mg, 24% yield, R_(t)=3.92 min, the faster eluting isomer) as ayellow solid and(S)-1-(6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)ethan-1-ol(10.5 mg, 26% yield, R_(t)=4.74 min, the slower eluting isomer) as ayellow solid. Absolute stereochemistry of the diastereomers wasarbitrarily assigned. Characterization of(R)-1-(6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)ethan-1-ol:LCMS m/z [M+H]⁺=497.1; ¹HNMR (400 MHz, CD₃OD): 7.78-7.80 (m, 1H),7.40-7.43 (m, 1H), 7.28-7.31 (m, 1H), 7.09-7.13 (m, 3H), 6.92-6.95 (m,1H), 5.05-5.13 (m, 1H), 3.91-3.99 (s, 3H), 3.65-3.80 (m, 1H), 3.40-3.50(m, 1H), 3.15-3.20 (m, 1H), 3.00-3.08 (m, 2H), 2.88-2.98 (m, 2H),2.70-2.75 (m, 1H), 2.08-2.12 (m, 2H), 1.89-2.05 (m, 2H), 1.55-1.60 (m,1H), 1.38-1.42 (m, 4H); SFC: e.e. =97.6%. Characterization of(S)-1-(6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)ethan-1-ol:LCMS m/z [M+H]⁺=497.1; ¹HNMR (400 MHz, CD₃OD): 7.78-7.80 (m, 1H),7.40-7.43 (m, 1H), 7.28-7.31 (m, 1H), 7.09-7.13 (m, 3H), 6.92-6.95 (m,1H), 5.05-5.13 (m, 1H), 3.91-3.99 (s, 3H), 3.65-3.80 (m, 1H), 3.40-3.50(m, 1H), 3.15-3.20 (m, 1H), 3.00-3.08 (m, 2H), 2.88-2.98 (m, 2H),2.70-2.75 (m, 1H), 2.08-2.12 (m, 2H), 1.89-2.05 (m, 2H), 1.55-1.60 (m,1H), 1.38-1.42 (m, 4H). SFC: e.e. =96.4%.

Example 143: Synthesis of(S)-1′-(3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

(R)—N-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(250 mg, 0.394 mmol, Intermediate CY), ethynylbenzene (47.5 μL, 0.4332mmol), ethylbis(propan-2-yl)amine (69.4 μL, 0.3978 mmol), iodocopper(3.74 mg, 0.0197 mmol) and XPhos-Pd-G4 (33.9 mg, 0.0394 mmol) were addedto MeCN (5 mL) in a sealed tube. The mixture was bubbled with N₂ for 5min and the reaction was stirred at 80° C. for 20 h. The solvent wasremoved in vacuo and the crude product was purified by columnchromatography (Si-12 g column, 25-100% EA/hep) to afford(R)-2-methyl-N-((1S)-1′-(3-(phenylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)propane-2-sulfinamide.LCMS m/z [M+H]⁺=609.4.

Step b:

(R)-2-methyl-N-[(3S)-1′-[1-(oxan-2-yl)-3-(2-phenylethynyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]propane-2-sulfinamide(120 mg, 0.197 mmol) in MeOH (2 mL) was charged with hydrogen chloride(492 μL, 1.97 mmol) and heated to 60° C. for 2 hr. The solvent wasremoved in vacuo and crude product purified by prep-HPLC (10-40%ACN/water/FA) to affordS)-1′-(3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(50 mg, 60% yield) as a white solid. LCMS m/z [M+H]⁺=421.6; ¹H NMR (400MHz, DMSO-d6) Shift 13.35-13.65 (m, 1H), 8.49 (s, 1H), 8.21 (s, 1H),7.58-7.65 (m, 2H), 7.44-7.49 (m, 3H), 7.31-7.36 (m, 1H), 7.16-7.23 (m,3H), 4.28-4.39 (m, 2H), 3.93 (s, 1H), 3.30 (br s, 2H), 3.11 (d, J=15.92Hz, 1H), 2.71 (d, J=15.66 Hz, 1H), 1.76-1.86 (m, 1H), 1.70 (dt, J=3.79,12.51 Hz, 1H), 1.55 (br d, J=12.63 Hz, 1H), 1.21 (br d, J=12.63 Hz, 1H).

Example 144: Synthesis of(S)-1′-(6-(2-chlorophenyl)-5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

Dissolved tert-butylN-[(3S)-1′-(5-amino-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(101 mg, 0.252 mmol, Intermediate CF) in 10 mL acetone then added2-bromo-1-(2-chlorophenyl)propan-1-one (80.8 μL, 0.503 mmol, CAS#75815-22-4) and heated the reaction at reflux for 16 hr. The solventwas then removed and the residue was dissolved in 6N HCl (12 mL) and thereaction was stirred at 100° C. for 1.5 hr. Then an additionalequivalent of 2-bromo-1-(2-chlorophenyl)propan-1-one (124 mg, 0.503mmol) was added and the reaction was stirred at 100° C. for 45 min, thenat rt for 48 h. The reaction mixture was concentrated in vacuo andpurified by prep HPLC (5-30% B, FA). To give(3S)-1′-[6-(2-chlorophenyl)-5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(8.20 mg, 0.0182 mmol). LCMS m/z [M+H]⁺=450.5; ¹H NMR (400 MHz, DMSO-d6)Shift 7.50-7.54 (m, 1H), 7.44-7.48 (m, 1H), 7.35-7.41 (m, 2H), 7.29-7.34(m, 1H), 7.14-7.21 (m, 3H), 3.90 (s, 1H), 3.69-3.79 (m, 2H), 3.41 (br d,J=3.03 Hz, 2H), 3.07 (d, J=15.66 Hz, 1H), 2.61-2.69 (m, 1H), 2.27 (s,3H), 1.83-1.92 (m, 1H), 1.77 (dt, J=4.29, 12.63 Hz, 1H), 1.53-1.60 (m,1H), 1.19 (br d, J=15.41 Hz, 1H).

Example 145: Synthesis of(S)-1′-(5-(2-chlorophenyl)thiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

Dissolved tert-butylN-[(3S)-1′-(5-bromo-1,3-thiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(48 mg, 0.103 mmol, Intermediate CG), (2-chlorophenyl)boronic acid (17.7mg, 0.114 mmol), potassium methaneperoxoate potassium hydride (28.9 mg,0.207 mmol) and palladium tetrakis (11.9 mg, 0.0103 mmol) in DMF/water(10:1). The reaction mixture was heated in a microwave at 100° C. for 30min. The reaction was partitioned between water and EtOAc, and themixture was extracted with EtOAc (2×). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography (0-100% EtOAcin heptanes) to give tert-butylN-[(3S)-1′-[5-(2-chlorophenyl)-1,3-thiazol-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(29.0 mg, 57% yield). This intermediate was then dissolved in DCM (750uL) then TFA (200 uL) was added and the reaction mixture was stirred atrt for 15 min. The reaction mixture was concentrated then purified byHPLC (10-40% B (FA)) to give(3S)-1′-[5-(2-chlorophenyl)-1,3-thiazol-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(14.9 mg, 37% yield). LCMS m/z [M+H]⁺=396.5; ¹H NMR (500 MHz, DMSO-d6)Shift 7.58 (dd, J=1.53, 7.93 Hz, 1H), 7.50-7.55 (m, 2H), 7.33-7.39 (m,2H), 7.27-7.31 (m, 1H), 7.19-7.24 (m, 3H), 4.03 (s, 1H), 3.84 (br d,J=13.12 Hz, 2H), 3.24-3.28 (m, 3H), 3.08 (d, J=15.86 Hz, 1H), 2.74 (d,J=15.86 Hz, 1H), 1.80-1.87 (m, 1H), 1.70-1.79 (m, 1H), 1.54 (br dd,J=1.37, 13.27 Hz, 1H), 1.28 (br d, J=12.81 Hz, 1H).

Example 146: Synthesis of(3S)-1′-[5-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

In a vial, weighed(3S)-1′-(5-chloropyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(52 mg, 0.165 mmol, Intermediate CH),1,2,3,4-tetrahydro-1,5-naphthyridine (24.3 mg, 0.182 mmol),9-{[5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenyl-λ⁵-phosphanyl}-8-methyl-8-aza-9-palladatricyclo[8.4.0.0²,⁷]tetradeca-1(14),2(7),3,5,10,12-hexaen-9-ylmethanesulfonate (15.8 mg, 0.0165 mmol), and (tert-butoxy)sodium (23.7mg, 0.248 mmol). The reaction mixture was evacuated and backfilled withN₂, then toluene (2 mL) was added and the reaction was stirred at 80° C.for 20 min. The reaction mixture was then concentrated, and the residuewas redissolved in DMSO and purified by reverse phase HPLC (5-30% B(FA)) to give(3S)-1′-[5-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(12.0 mg, 18% yield) as a yellow solid. LCMS m/z (M+H)⁺=413.6; ¹H NMR(500 MHz, DMSO-d6) Shift 8.24 (s, 2H), 8.14 (d, J=1.22 Hz, 1H), 8.07 (d,J=1.22 Hz, 1H), 7.87 (dd, J=1.22, 4.58 Hz, 1H), 7.36-7.41 (m, 1H),7.17-7.27 (m, 3H), 7.09 (dd, J=1.22, 8.24 Hz, 1H), 6.93 (dd, J=4.58,8.24 Hz, 1H), 4.12 (dt, J=3.97, 8.39 Hz, 2H), 4.03 (s, 1H), 3.61-3.65(m, 2H), 3.06-3.14 (m, 3H), 2.89 (t, J=6.41 Hz, 2H), 2.76 (d, J=15.86Hz, 1H), 1.98-2.04 (m, 2H), 1.79 (dt, J=4.27, 12.51 Hz, 1H), 1.70 (dt,J=4.12, 12.43 Hz, 1H), 1.50 (br d, J=11.90 Hz, 1H), 1.27 (br d, J=12.81Hz, 1H).

Example 147: Synthesis of(S)-1′-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

The compound of(S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(200.0 mg, 556 μmol, Intermediate CI), 2,3-dichlorobenzene-1-thiol(129.0 mg, 722 μmol, CAS #17231-95-7), Pd₂(dba)₃ (50.9 mg, 55.6 μmol),XantPhos (64.2 mg, 111 μmol), and DIPEA (485 μL, 2.78 mmol) were addedin dioxane (10 mL). The reaction mixture was evacuated and refilled 3times with N₂. The reaction mixture was stirred at 110° C. for 12 hours.Then H₂O (20 mL) was added and the reaction mixture was extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated togive(S)-1′-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine((300 mg, quant. crude yield). LCMS m/z (M+53)=509.

Step b:

(S)-1′-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(254.0 mg, 555 μmol), di-tert-butyl dicarbonate (328 μL, 1.10 mmol) andTEA (228 μL, 1.66 mmol) were dissolved in DCM (10 mL), and the mixturewas stirred at rt for 13 hours. The reaction mixture was washed with H₂O(10 mL×2), brine (15 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byprep-TLC (Petroleum ether:Ethyl acetate=3:1) to afford tert-butylN-[(3S)-1′-{5-[(2,3-dichlorophenyl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(95.0 mg, 30.7% yield) as a yellow solid. LCMS m/z (M+H)⁺=456.9.

Step c:

The compound of tert-butylN-[(3S)-1′-{5-[(2,3-dichlorophenyl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100.0 mg, 179 μmol) was added in HCl/MeOH (5.0 mL, 4M) and the mixturewas stirred at 25° C. for 0.5 h. The mixture was then concentrated togive a residue which was purified by prep-HPLC (HCl) to give(3S)-1′-{5-[(2,3-dichlorophenyl)sulfanyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (35.5 mg, 85% yield) as a yellow solid. LCMS m/z(M+H)⁺=457.0; ¹HNMR (400 MHz, DMSO-d₆): δ 8.53 (s, 3H), 8.49 (s, 1H),8.30 (s, 1H), 7.57˜7.60 (m, 1H), 7.46˜7.49 (m, 1H), 7.23˜7.38 (m, 4H),6.84˜6.87 (m, 1H), 4.35˜4.39 (m, 2H), 4.25˜4.30 (m, 1H), 3.19˜3.28 (m,3H), 2.98˜3.03 (m, 1H), 1.73˜1.85 (m, 2H), 1.51˜1.59 (m, 2H).

Example 148: Synthesis of(S)—N4-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N4-methylpyridine-2,4-diamine

Step a:

A solution of tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(300.0 mg, 475.0 μmol, Intermediate J), 2-chloro-N-methylpyridin-4-amine(87.9 mg, 617.0 μmol, Intermediate CM), XantPhos-Pd-G4 (45.6 mg, 47.5umol) and Cs₂CO₃ (308.0 mg, 950.0 umol) in PhMe (10.0 mL) was stirred at90° C. for 12 hours under N₂. The reaction mixture was then poured intoH₂O (30.0 mL) and extracted with EtOAc (50.0 mL×2). The combined organiclayers were washed with brine (50.0 mL), dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure togive a brown residue. The residue was purified by flash silica gelchromatography (12 g column, ethyl acetate in petroleum ether from 0% to35%) to give tert-butylN-[(3S)-1′-{3-[(2-chloropyridin-4-yl)(methyl)amino]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(230.0 mg, 75% yield) as a yellow solid. LCMS m/z (M+H)⁺=645.1.

Step b:

A solution of tert-butylN-[(3S)-1′-{3-[(2-chloropyridin-4-yl)(methyl)amino]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(150.0 mg, 232.0 μmol), diphenylmethanimine (63.0 mg, 348.0 μmol),Pd₂(dba)₃ (21.2 mg, 23.2 umol), XPhos (44.2 mg, 92.8 umol) and t-BuONa(66.8 mg, 696.0 umol) in PhMe (5.0 mL) was stirred at 100° C. for 12hours under N₂. The reaction mixture was concentrated under reducedpressure. The residue was triturated with EtOAc (10.0 mL), filtered andthe filtrate was concentrated to give tert-butylN-[(3S)-1′-[3-({2-[(diphenylmethylidene)amino]pyridin-4-yl}(methyl)amino)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 137% crude yield) as an orange solid. LCMS m/z (M+H)⁺=790.2.

Step c:

A solution of tert-butylN-[(3S)-1′-[3-({2-[(diphenylmethylidene)amino]pyridin-4-yl}(methyl)amino)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 316.0 μmol) in HCl/MeOH (6.0 mL, 4 M) was stirred at 20° C.for 2 hours. The reaction mixture was poured into H₂O (20.0 mL) andextracted with EtOAc (30.0 mL×2). The aqueous phase was concentratedunder reduced pressure. The residue was diluted with MeOH (5.0 mL),purified by prep-HPLC (HCl) and preparative SFC.(S)—N₄-(6-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N₄-methylpyridine-2,4-diamine(9.7 mg, 35% yield) was obtained as a yellow solid. LCMS m/z(M+H)⁺=442.1; ¹HNMR (400 MHz, CD₃OD): 8.34 (s, 1H), 7.54-7.56 (m, 1H),7.41-7.43 (m, 1H), 7.26-7.30 (m, 3H), 6.31-6.34 (m, 1H), 6.13-6.14 (m,1H), 4.41-4.48 (m, 2H), 4.10-4.14 (m, 1H), 3.53 (s, 3H), 3.38-3.45 (m,2H), 3.19-3.24 (m, 1H), 2.93-2.98 (m, 1H), 1.82-1.92 (m, 2H), 1.55-1.69(m, 2H). SFC: e.e. =96.9%, R_(t)=2.23 min. Column: ChiralCel OD-3150×4.6 mm I.D., 3 um, Mobile phase: 40% of Methanol (0.1%Ethanolamine), Flow rate: 2.5 mL/min Column temperature: 40° C.

Example 149: Synthesis of(3S)-1′-{5-methyl-3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

Tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(300.0 mg, 475.0 μmol, Intermediate J),6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (122.0mg, 570.0 μmol, Intermediate X), Xantphos-Pd-G4 (45.6 mg, 47.5 μmol, CAS#1599466-81-5) and Cs₂CO₃ (462.0 mg, 1.42 mmol) were added in PhMe (16mL). The reaction mixture was evacuated and refilled 3 times with N₂ andstirred at 100° C. for 12 hours. The reaction mixture was concentratedunder reduced pressure and purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:0 to 100:90) to afford tert-butylN-[(3S)-1′-{3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(320.0 mg, 94% yield) as a yellow solid. LCMS m/z (M+H)⁺=717.3.

Step b:

Tert-butylN-[(3S)-1′-{3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(320.0 mg, 446.0 μmol) was dissolved in the mixture of ACN (10 mL) andAcOH (10 mL), NBS (79.3 mg, 446.0 μmol) was added, and the reactionmixture was stirred at 25° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure and purified by flash silica gelchromatography (petroleum ether:ethyl acetate=100:30 to 0:100) to affordtert-butylN-[(3S)-1′-{5-bromo-3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(320.0 mg, 90% yield) as a yellow solid. LCMS m/z (M+H)⁺=797.2.

Step c:

tert-butylN-[(3S)-1′-{5-bromo-3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(220.0 mg, 276.0 μmol), Pd(dppf)Cl₂ (20.2 mg, 27.6 μmol), Cs₂CO₃ (179.0mg, 552.0 μmol) and MeB (OH)₂ (81.4 mg, 1.38 mmol) were added in themixture of dioxane (16 mL) and H₂O (4 mL). The reaction mixture wasevacuated and refilled 3 times with N₂ and stirred at 100° C. for 12hours. The reaction mixture was concentrated under reduced pressure andpurified by flash silica gel chromatography (petroleum ether:ethylacetate=100:50 to 100:100) to afford tert-butylN-[(3S)-1′-{5-methyl-3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(180.0 mg, 90% yield) as a yellow solid. LCMS m/z (M+H)⁺=731.3.

Step d:

Tert-butylN-[(3S)-1′-{5-methyl-3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(180.0 mg, 246.0 μmol) was added in 4N HCl/MeOH (6 mL), the reactionmixture was stirred at 25° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure and purified by prep-HPLC (HCl) toafford(3S)-1′-{5-methyl-3-[6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl]-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (45.4 mg, 34% yield) as a yellow solid. LCMS m/z(M+H)⁺=547.1. ¹HNMR (400 MHz, Methanol-d₄): δ 8.50 (s, 1H), 7.99 (d,J=6.8 Hz, 1H), 7.63 (d, J=6.8 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.46-7.34(m, 3H), 4.60-4.44 (m, 3H), 3.54-3.41 (m, 2H), 3.24 (s, 2H), 2.04-1.68(m, 4H).

Example 150: Synthesis of(S)-2-((6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)(methyl)amino)propanenitrile

Step a:

A mixture of tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(500.0 mg, 792.0 μmol, Intermediate J), (2S)-2-(methylamino)propanoicacid (244.0 mg, 2.4 mmol, CAS #29475-64-7), K₂CO₃ (327.0 mg, 2.40 mmol)and nano-Cu powder (100.0 mg, 1.60 mmol) in NMP (10.0 mL) was stirredunder microwave irradiation at 130° C. for 1.5 hours. The reactionmixture was then diluted with H₂O (100.0 mL), adjusted to pH=5-6 withHCl (2N) and extracted with DCM (100.0 mL×3). The combined organicphases were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to giveN-(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N-methyl-L-alanine(1.00 g, 104% crude yield) as a yellow oil. LCMS m/z (M+H)⁺=606.3.

Step b:

A mixture of(2S)-2-({6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl}(methyl)amino)propanoicacid (1.00 g, crude), ammonium 1H-1,2,3-benzotriazol-1-olate (375.0 mg,2.5 mmol, CAS #63307-62-0) and EDCI (473.0 mg, 2.5 mmol) in DMF (10.0mL) was stirred at 20° C. for 12 hours under N₂. The reaction wasdiluted with H₂O (200.0 mL), and extracted with EtOAc (150.0 mL×3). Thecombined organic phase were washed with brine (300.0 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by flash silica gelchromatography (ethyl acetate in petroleum ether=0˜90%) to affordtert-butyl((1S)-1′-(3-(((S)-1-amino-1-oxopropan-2-yl)(methyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(700.0 mg) as a yellow oil. LCMS m/z (M+H)⁺=605.3.

Step c:

To a solution of tert-butyl((1S)-1′-(3-(((S)-1-amino-1-oxopropan-2-yl)(methyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(350.0 mg, 578.0 μmol) and Et₃N (158.0 μL, 1.2 mmol) in DCM (10.0 mL)was added TFAA (161.0 μL, 1.2 mmol) dropwise at 0° C. and the mixturewas stirred at 25° C. for 12 hours. The reaction mixture was quenchedwith H₂O (50.0 mL) and extracted with DCM (50.0 mL×2). The combinedorganic layers were washed with brine (50.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash silica gel chromatography(ethyl acetate in petroleum ether=0˜30%) to afford tert-butylN-[(3S)-1′-(3-{[(1S)-1-cyanoethyl](methyl)amino}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100.0 mg, 28% yield) as a yellow oil. LCMS m/z (M+H)⁺=609.1.

Step d:

The tert-butylN-[(3S)-1′-(3-{[(1S)-1-cyanoethyl](methyl)amino}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 204.0 μmol) dissolved in CH₃CN (2.0 mL) and HCl (2.0 mL, 2N)and stirred at 25° C. for 12 hours. The mixture was adjusted pH=8˜9 byNaHCO₃ (aq.) and extracted with EtOAc (50.0 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC (NH₃.H₂O) to afford(S)-2-((6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)(methyl)amino)propanenitrile(23.4 mg, 28% yield) as a light yellow solid. LCMS m/z (M+H)⁺=403.0;¹HNMR (400 MHz, CDCl₃): δ 9.85 (s, 1H), 8.04 (s, 1H), 7.31-7.38 (m, 1H),7.19-7.26 (m, 3H), 5.90 (q, J=7.2 Hz, 1H), 4.20-4.33 (m, 2H), 4.01 (s,1H), 3.24-3.38 (m, 2H), 3.20 (s, 3H), 3.05-3.16 (m, 1H), 2.69-2.81 (m,1H), 1.75-1.96 (m, 3H), 1.66 (d, J=7.2 Hz, 3H), 1.37-1.46 (m, 1H).

Example 151: Synthesis of(2S)-2-({6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}(methyl)amino)propanamide

Step a:

Tert-butylN-[(3S)-1′-(3-{[(1S)-1-carbamoylethyl](methyl)amino}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 330.0 μmol, synthesized via Steps a-b of Example 150) wasdissolved in EtOAc (5.0 mL) and HCl/EtOAc (3.0 mL, 4N) and stirred at25° C. for 12 hours. The mixture was diluted with H₂O (10.0 mL),adjusted pH=8-9 by anhydrous Na₂CO₃ and extracted with EtOAc (50.0mL×3). The combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (FA) to afford(2S)-2-({6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-3-yl}(methyl)amino)propanamideformate (12.3 mg, 26.3 μmol, 8% yield) as a yellow solid. LCMS m/z(M+H)⁺=421.2; ¹HNMR (400 MHz, DMSO_d₆): δ 11.82 (s, 1H), 8.24 (s, 1H),8.18 (s, 1H), 7.31-7.42 (m, 1H), 7.17-7.27 (m, 3H), 7.02 (s, 1H), 5.23(q, J=6.9 Hz, 1H), 4.2-4.42 (m, 2H), 4.00 (s, 1H), 3.08-3.20 (m, 3H),2.97 (s, 3H), 2.75 (m, 1H), 1.62-1.84 (m, 2H), 1.46-1.56 (m, 1H),1.18-1.31 (m, 4H).

Example 152: Synthesis of(3S)-1′-[5-methyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To a mixture of tert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(500.0 mg, 0.8 mmol, Intermediate J) and piperidine (80.8 mg, 1.0 mmol)in toluene (10.0 mL) were added XantPhos-Pd-G4 (76.1 mg, 79.2 μmol, CAS#1621274-19-8) and Cs₂CO₃ (513.0 mg, 1.6 mmol). The reaction mixture wasevacuated and refilled 3 times using N₂. The reaction mixture wasstirred at 100° C. for 12 hours. The reaction mixture was concentratedunder reduced pressure to give a residue which was purified by columnchromatography (petroleum ether:ethyl acetate=100:0 to 100:30) to affordtert-butylN-[(3S)-1′-[1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 54% yield) as a yellow solid. LCMS m/z (M+H)⁺=588.3.

Step b:

To a solution of tert-butylN-[(3S)-1′-[1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 0.4 mmol) in MeCN (5.0 mL) and AcOH (3.0 mL) was added NBS(90.6 mg, 0.5 mmol). The reaction mixture was stirred at 25° C. for 12hours. The reaction mixture was concentrated under reduced pressure togive a residue which was purified by column chromatography (petroleumether:ethyl acetate=100:0 to 100:30). The product tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(130.0 mg, 46% yield) was obtained as a yellow solid. LCMS m/z(M+H)⁺=666.1.

Step c:

To a mixture of tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(130.0 mg, 0.2 mmol) and trimethylboroxine (48.9 mg, 0.4 mmol) indioxane (5.0 mL) and H₂O (0.5 mL) was added Pd(dppf)Cl₂ (14.2 mg, 19.5μmol) and K₂CO₃ (53.7 mg, 0.4 mmol). The reaction mixture was purgedwith N₂ for 3 min and stirred at 100° C. for 12 hours under N₂. Thereaction mixture was then concentrated under reduced pressure to givethe residue which was purified by column chromatography (petroleumether:ethyl acetate=100:0 to 100:30). The product tert-butylN-[(3S)-1′-[5-methyl-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(80.0 mg, 68% yield) was obtained as a yellow solid. LCMS m/z(M+H)⁺=602.3.

Step d:

A solution of tert-butylN-[(3S)-1′-[5-methyl-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(75.0 mg, 0.1 mmol) in HCl/MeOH (5.0 mL, 4M) was stirred at 30° C. for 2hours. The reaction mixture was concentrated under reduce pressure. Theresidue was dissolved with MeOH (5.0 mL) and purified by prep-HPLC (HCl)to give(3S)-1′-[5-methyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (40.0 mg, 71% yield) as a yellow solid. LCMS m/z(M+H)⁺=418.1; ¹HNMR (400 MHz, Methanol-d₄): 7.54-7.56 (m, 1H), 7.35-7.45(m, 3H), 7.47 (m, 1H), 3.99-4.03 (m, 1H), 3.85-3.97 (m, 5H), 3.36-3.40(m, 1H), 3.25-3.32 (m, 1H), 3.21 (s, 2H), 2.66 (s, 3H), 2.03-2.11 (m,1H), 1.91-1.98 (m, 1H), 1.75-1.87 (m, 7H), 1.68-1.72 (m, 1H).

Example 153: Synthesis of2-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl}acetonitrile

Step a:

To the mixture of{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (300.0 mg, 426.0 μmol, Intermediate K) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (83.0 mg,426.0 μmol, CAS #928664-98-6) in dioxane (8 mL) and H₂O (2 mL) wereadded Pd(dppf)Cl₂ (31.1 mg, 42.6 μmol) and K₂CO₃ (146.0 mg, 1.0 mmol)under N₂. The mixture was stirred at 100° C. under N₂ for 12 hours. Themixture was concentrated under reduced pressure to give a yellow solid.The residue was purified by flash silica gel chromatography (petroleumether/EtOAc=1/0 to 1/1) to give tert-butylN-[(3S)-1′-[3-(cyanomethyl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(90.0 mg, 37% yield) as a yellow solid. LCMS m/z (M+H)⁺=574.1.

Step b:

To the mixture of tert-butylN-[(3S)-1′-[3-(cyanomethyl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(60.0 mg, 104.0 μmol) in DCM (1 mL) was added TFA (1 mL). The mixturewas stirred at 30° C. for 2 hours. The mixture was adjusted to pH=8 withsolid Na₂CO₃ and purified by pre-HPLC (HCOOH) to give2-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl}acetonitrileformate (15.0 mg, 33% yield) as a white solid. LCMS m/z (M+H)⁺=390.2; ¹HNMR (400 MHz, CD₃OD-d₄): 8.54 (s, 1H), 7.53-7.51 (m, 1H), 7.42-7.34 (m,3H), 4.83 (s, 2H), 4.41 (s, 1H), 4.27 (s, 2H), 3.85-3.73 (m, 2H),3.31-3.11 (m, 4H), 2.10-1.97 (m, 2H), 1.79-1.68 (m, 2H).

Example 154: Synthesis of6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

Step a:

To the mixture of{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4(300.0 mg, 426.0 μmol, Intermediate K) and Zn(CN)₂ (100.0 mg, 852.0μmol) in DMF (10 mL) was added [(t-Bu)₃P]₂Pd (43.5 mg, 85.2 μmol, CAS#53199-31-8) under N₂. The mixture was stirred at 110° C. under N₂ for12 hours. The mixture was then poured into water (50 mL) and extractedwith EtOAc (50 mL×3). The organic layers were washed with brine (60mL×3) and dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a yellow solid. The residue was purified byflash silica gel chromatography (petroleum ether/EtOAc=1/0 to 3/1) togive{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-cyano-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (250.0 mg, 98% yield) as a yellow solid. LCMS m/z (M+Na)⁺=624.1.

Step b:

A mixture of{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-cyano-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (150.0 mg, 249.0 μmol) in HCl/EtOAc (2 mL, 4 M) was stirred at30° C. for 12 hours. The mixture was concentrated under reduced pressureto give{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-cyano-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate hydrochloride (113.0 mg, 100% yield) as a brown solid. LCMS m/z(M+Na)⁺=440.0.

Step c:

To the mixture of{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-cyano-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate hydrochloride (113.0 mg, 248.0 μmol) in THE (3 mL) and H₂O (1mL) was added LiOH H₂O (31.2 mg, 744.0 μmol). The mixture was stirred at30° C. for 12 hours. The mixture was then concentrated under reducedpressure to give a yellow oil. The residue was purified by prep-HPLC(HCOOH) to give6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileformate (35.0 mg, 34% yield) as a white solid. LCMS m/z (M+Na)+=398.0;¹H NMR (400 MHz, CD₃OD-d₄): 8.54 (s, 1H), 7.52-7.50 (m, 1H), 7.40-7.34(m, 3H), 4.83 (s, 2H), 4.40 (s, 1H), 3.92-3.80 (m, 2H), 3.33-3.11 (m,4H), 2.10-1.96 (m, 2H), 1.79-1.68 (m, 2H).

Example 155: Synthesis of6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(hydroxymethyl)-N-methyl-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide

Step a:

The mixture of{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (500.0 mg, 711.0 μmol, Intermediate K), MeNH₂.HCl (475.0 mg, 7.1mmol), Pd(dppf)Cl₂ (52.0 mg, 71.1 μmol) and TEA (2 mL) in MeOH (20 mL)was evacuated and refilled 3 times using CO, then stirred at 80° C. for12 hours under CO (50 psi). The mixture was concentrated under reducedpressure and the residue was purified by column chromatography(DCM/MeOH=1:0˜10:1) to afford 170.0 mg of tert-butyl((1S)-1′-(5-(hydroxymethyl)-3-(methylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(170.0 mg, 66% purity, 27% yield) as a brown solid. LCMS m/z(M+H)⁺=592.2.

Step b:

The mixture of tert-butylN-[(3S)-1′-[5-(hydroxymethyl)-3-(methylcarbamoyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(170.0 mg, 66% purity, 189.0 μmol) in HCl/EtOAc (4M, 3 mL) was stirredat 30° C. for 1 hour. The mixture was concentrated under reducedpressure. The residue was diluted with EtOAc (10 mL) and adjusted topH=8 with K₂CO₃. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. The mixture was purified byprep-HPLC (FA) to afford6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(hydroxymethyl)-N-methyl-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide;formic acid (17.3 mg, 20% yield) as a yellow solid. LCMS m/z(M+H)⁺=408.1; ¹HNMR (400 MHz, CDCl₃+MeOD-d₄): δ 8.27 (br, 1H), 7.36-7.32(m, 1H), 7.24-7.20 (m, 3H), 4.76-4.74 (m, 2H), 4.09 (m, 1H), 3.31-3.30(m, 2H), 3.16-2.83 (m, 7H), 1.62-1.59 (m, 2H), 1.54-1.50 (m, 2H).

Example 156: Synthesis of{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol

Step a:

(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate (150 mg, 213 μmol, Intermediate K), K₃PO₄.3H₂O (529 mg, 1.06mmol), trimethylboroxine (267 mg, 2.13 mmol, CAS #823-96-1) andPd(PPh₃)₄(24.6 mg, 21.3 μmol) were dissolved in PhMe/H₂O (10 mL/1 mL).The combined reaction mixture was evacuated and refilled for 3 timesusing N₂. The reaction mixture was stirred at 100° C. for 12 hours. Thereaction mixture was diluted with ethyl acetate (30 mL) and H₂O (20 mL).The partitioned layers were separated and the aqueous phase wasextracted with ethyl acetate (30 mL×3). The combined organic layers werewashed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (petroleum ether:ethyl acetate=100:0 to 100:40) toafford(6-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methylacetate (130 mg, 112% crude yield) as a yellow oil. LCMS m/z(M+H)⁺=591.2.

Step b:

{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (120 mg, 203 μmol) was added into aq. HCl (14 mL, 4 N) and thereaction mixture was stirred at 25° C. for 6 hours. The reaction mixturewas adjusted to pH=7˜8 with saturated solution of Na₂CO₃. The mixturewas purified by prep-HPLC (NH₃.H₂O) to give{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol(1.40 mg, 2% yield). LCMS m/z (M+H)⁺=365.1; ¹H NMR (400 MHz, CD₃OD)δ7.34-7.37 (m, 1H), 7.18-7.20 (m, 3H), 4.76 (s, 3H), 3.65-3.66 (m, 1H),3.32-3.37 (m, 2H), 3.13-3.26 (m, 3H), 3.04-3.07 (m, H), 2.77 (s, 3H),1.96-1.97 (m, 2H), 1.48-1.61 (m, 1H), 1.47-1.48 (m, 1H).

Example 157: Synthesis of(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)methyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To the reaction mixture of(R)—N—((S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(400.0 mg, 0.9 mmol, synthesized via Step a of Intermediate BR) in THE(10 mL) was added CuCl (341.0 mg, 3.5 mmol), and the reaction mixturewas stirred at 25° C. for 0.5 h. Then n-BuLi (1.38 mL, 3.5 mmol, 2.5 Min THF) was added into the reaction mixture at −78° C. under N₂atmosphere. The resulting mixture was stirred at −78° C. for 1 hour.Next, 2,3-dichloropyridine-4-carbaldehyde (758.0 mg, 4.3 mmol, CAS#884495-41-4) was added and the resulting mixture was stirred at −78° C.for 1 hour. The reaction mixture was quenched with saturated NH₄Cl (20mL) and extracted with EtOAc (40 mL×2). The combined organic layers werewashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (20 g column, EtOAc inpetroleum ether from 0% to 1000%) to give(R)—N-((1S′)-1′-(5-((2,3-dichloropyridin-4-yl)(hydroxy)methyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(155.0 mg, 3200 yield) as a yellow oil. LCMS m/z (M+H)⁺=560.0.

Step b:

To the reaction mixture of(R)—N-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)(hydroxy)methyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(155.0 mg, 0.3 mmol) in THF (1 mL) was added PBr₃ (74.8 mg, 0.3 mmol) at25° C. The resulting mixture was stirred at 25° C. for 0.5 hour, andthen stirred at 80° C. for 2 hours. The combined reaction mixture wasquenched by H₂O (15 mL) at 0° C. and adjusted to pH=10-11 with solidNa₂CO₃. The reaction mixture was extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-HPLC (basic conditions)to give(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)methyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(3.7 mg, 3% yield) as an off-white solid. LCMS m/z (M+H)⁺=440.0; ¹H NMR(400 MHz, CDCl₃) δ 8.20 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 8.02 (s, 1H),7.34-7.33 (m, 1H), 7.24-7.16 (m, 3H), 7.14-7.10 (m, 1H), 4.21-4.11 (m,4H), 3.99 (s, 1H), 3.24-3.15 (m, 2H), 3.09 (d, J=15.6 Hz, 1H), 2.74 (d,J=16.0 Hz, 1H), 1.90-1.79 (m, 3H), 1.41-1.34 (m, 1H).

Example 158: Synthesis of{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-methoxy-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol

Step a:

To the mixture of K₂CO₃ (146.0 mg, 1.1 mmol) in MeOH (10 mL) was added{6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (250.0 mg, 355.0 μmol, Intermediate K). The mixture was stirredat 20° C. for 12 hours. The mixture was then concentrated under reducedpressure. The residue was purified by column chromatography (petroleumether/ethyl acetate=1:0˜3:1) to afford tert-butylN-[(3S)-1′-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(210.0 mg, 90% yield) as a yellow oil. LCMS m/z (M+H)⁺=661.1.

Step b:

The mixture of tert-butylN-[(3S)-1′-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(190.0 mg, 287.0 μmol) and TBSCI (64.5 mg, 430.0 μmol) in TEA (1 mL) andDCE (5 mL) was stirred at 70° C. for 2 hours. The mixture was dilutedwith H₂O (20 mL), then extracted with EtOAc (20 mL×2). The organic layerwas washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=10:0˜10:1) to affordtert-butylN-[(3S)-1′-(5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 90% yield) as a yellow oil. LCMS m/z (M+H)⁺=775.1.

Step c:

The mixture of tert-butylN-[(3S)-1′-(5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(140.0 mg, 180.0 μmol), Cs₂CO₃ (117.0 mg, 360.0 μmol), CuI (3.4 mg, 18.0μmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (8.5 mg, 36.0 μmol) inMeOH (5 mL) was stirred under microwave irradiation at 100° C. for 2hours. The TBS group was removed and the hydroxyl group was oxidized toaldehyde in the reaction course. The mixture was concentrated underreduced pressure. The residue was purified by column chromatography(petroleum ether/ethyl acetate=1:0˜5:1) to afford tert-butylN-[(3S)-1′-[5-formyl-3-methoxy-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(40.0 mg, 40% yield) as a yellow oil. LCMS m/z (M+H)⁺=563.2.

Step d:

To the mixture of tert-butylN-[(3S)-1′-[5-formyl-3-methoxy-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(40.0 mg, 71.0 μmol) in MeOH (5 mL) was added NaBH₄ (5.4 mg, 142.0 μmol)at 0° C. under N₂ atmosphere. The mixture was stirred at 0° C. for 0.5hours. The mixture was then quenched with saturated NH₄Cl (20 mL), andextracted with EtOAc (20 mL). The organic layer was washed with brine(10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford tert-butylN-[(3S)-1′-[5-(hydroxymethyl)-3-methoxy-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(35.0 mg, 88% yield) as a yellow solid. LCMS m/z (M+H)⁺=565.2.

Step e:

The mixture of tert-butylN-[(3S)-1′-[5-(hydroxymethyl)-3-methoxy-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(35.0 mg, 61.9 μmol) in DCM (3 mL) and TFA (0.3 mL) was stirred at 30°C. for 12 hours. Then the mixture was concentrated under reducedpressure. The residue was diluted with EtOAc (10 mL), and adjusted pH=7by K₂CO₃. The mixture was filtered and the filtrate was concentratedunder reduced pressure. The mixture was then purified by prep-HPLC(NH₃.H₂O) to afford{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-3-methoxy-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol(6.7 mg, 29% yield) as a white solid. LCMS m/z (M+H)⁺=381.0; ¹HNMR (400MHz, MeOD-d₄): δ 7.42-7.39 (m, 1H), 7.26-7.20 (m, 3H), 4.77 (s, 2H),4.12 (s, 3H), 4.02 (s, 1H), 3.75-3.72 (m, 2H), 3.24-2.79 (m, 4H),2.05-1.96 (m, 2H), 1.67-1.32 (m, 2H).

Example 159: Synthesis of{6-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol

Step a:

To a mixture of{6-[(3R)-3-{[(tert-butoxy)carbonyl]amino}-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methylacetate (200 mg, 0.3 mmol, Intermediate CX) in dioxane (5.0 mL) wereadded Cs₂CO₃ (183 mg, 0.6 mmol), XantPhos-Pd-G4 (21.5 mg, 28.3 μmol) andEt₃SiH (223 μL, 1.4 mmol). The reaction mixture was purged with N₂ for 3min and stirred at 100° C. for 12 hours under N₂. The reaction mixturewas concentrated under reduced pressure to give a residue which waspurified by column chromatography (petroleum ether:ethyl acetate=100:0to 100:50). tert-butylN-[(3R)-1′-[5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(100 mg, 66% yield) was obtained as a yellow solid. LCMS m/z(M+H)⁺=537.2.

Step b:

A solution of tert-butylN-[(3R)-1′-[5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(100 mg, 186 μmol) in THF (3.0 mL) and HCl/H₂O (3 mL, 2M) was stirred at30° C. for 12 hours. The reaction mixture was concentrated under reducedpressure to give a residue. The residue was dissolved with H₂O (5.0 mL)and adjusted to pH=8 with solid K₂CO₃, then purified by prep. HPLC(NH₃.H₂O).{6-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol(10.0 mg, 15% yield) was obtained as a white solid. LCMS m/z(M+H)⁺=353.1; ¹HNMR (400 MHz, Methanol-d₄): 8.13 (s, 1H), 7.40-7.42 (m,1H), 7.18-7.22 (m, 1H), 6.90-6.94 (m, 1H), 6.80-6.82 (m, 1H), 4.83 (s,2H), 4.17 (s, 1H), 3.80-3.84 (m, 1H), 3.70-3.74 (m, 1H), 3.42-3.49 (m,2H), 2.15-2.23 (m, 1H), 2.00-2.08 (m, 2H), 1.80-1.90 (m, 1H).

Example 160: Synthesis of(3S)-1′-[5-methyl-3-(morpholin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To the mixture of tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(300.0 mg, 475.0 μmol, Intermediate J) and morpholine (82.7 mg, 950.0μmol) in toluene (10.0 mL) were added Cs₂CO₃ (338.0 mg, 1.0 mmol),RuPhos (33.2 mg, 71.2 μmol, CAS #787618-22-8) and RuPhos-Pd-G4 (40.3 mg,47.5 μmol, CAS #1599466-85-9) under N₂. The mixture was stirred at 100°C. under N₂ for 12 hours. The mixture was then concentrated underreduced pressure and purified by flash silica gel chromatography(petroleum ether/EtOAc=1/0 to 1/1) to give tert-butylN-[(3S)-1′-[3-(morpholin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(250.0 mg, 89% yield) as a brown solid. LCMS m/z (ESI⁺) (M+Na)=612.2.

Step b:

To the mixture of tert-butylN-[(3S)-1′-[3-(morpholin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(230.0 mg, 390.0 μmol) in ACN (4.0 mL) and AcOH (4.0 mL) was added NBS(72.8 mg, 409.0 μmol) at −20° C. under N₂. The mixture was stirred at−20° C. under N₂ for 1 hour. The mixture was concentrated under reducedpressure to give a brown oil. The oil was adjusted to pH=8 with thesaturated NaHCO₃ and the mixture was extracted with EtOAc (40.0 mL×3).The combined organic layers were washed with brine (50.0 mL) and driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a brown oil. The residue was purified by flash silica gelchromatography (petroleum ether/EtOAc=1/0 to 3/1) to give tert-butylN-[(3S)-1′-[5-bromo-3-(morpholin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(140.0 mg) as a brown oil. LCMS m/z (M+H)⁺=668.1, 670.1.

Step c:

To the mixture of tert-butylN-[(3S)-1′-[5-bromo-3-(morpholin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 179.0 μmol) and K₂CO₃ (61.6 mg, 447.0 μmol) in dioxane (5 mL)and H₂O (0.5 mL) were added Pd(dppf)Cl₂ (13.0 mg, 17.9 μmol, CAS#72287-26-4) and trimethylboroxine (49.7 μL, 358.0 μmol, CAS #823-96-1)under N₂. The mixture was stirred at 90° C. under N₂ for 12 hours. Themixture was concentrated under reduced pressure and purified by flashsilica gel chromatography (petroleum ether/EtOAc=1/0 to 3/1) to givetert-butylN-[(3S)-1′-[5-methyl-3-(morpholin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(80.0 mg, 74% yield) as a brown solid. LCMS m/z (M+H)⁺=604.2.

Step d:

A mixture of tert-butylN-[(3S)-1′-[5-methyl-3-(morpholin-4-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(80.0 mg, 132.0 μmol) in HCl/EtOAc (4 mL, 4 M) was stirred at 30° C. for12 hours. The mixture was concentrated under reduced pressure to give abrown solid. The solid in EtOAc (10.0 mL) was stirred at 20° C. for 10min. The mixture was filtered and filter cake was lyophilized to give(3S)-1′-[5-methyl-3-(morpholin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (48.0 mg, 80% yield) as a brown solid. LCMS m/z(M+H)⁺=420.0. ¹H NMR (400 MHz, CD₃OD-d₄): 7.54 (d, J=7.2 Hz, 1H),7.45-7.35 (m, 3H), 4.47 (s, 1H), 3.91-3.87 (m, 5H), 3.82-3.80 (m, 5H),3.28-7.25 (m, 2H), 3.20 (s, 2H), 2.64 (s, 3H), 2.09-2.03 (m, 2H),1.96-1.68 (m, 2H).

Example 161: Synthesis of(3R)-1′-[5-methyl-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine

Step a:

A solution of (3R)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminedihydrochloride (1.10 g, 3.96 mmol, Intermediate CB),1-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine(1.46 g, 3.96 mmol, Intermediate AA) and TEA (3.31 mL. 23.7 mmol) inDMSO (25.0 mL) was stirred at 80° C. for 4 hours. To the mixture wasadded Boc₂O (1.69 g, 7.78 mmol). The reaction mixture was stirred at 20°C. for 0.5 hour. The reaction mixture was then poured into H₂O (250.0mL) and extracted with EtOAc (100.0 mL×2). The combined organic layerswere washed with brine (200.0 mL), dried over anhydrous Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure to give aresidue. The residue was purified by flash silica gel chromatography (40g, ethyl acetate in petroleum ether from 0% to 65%) to give tert-butylN-[(3R)-1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(1.40 g, 56% yield) as a yellow solid. LCMS m/z (M+H)⁺=639.1.

Step b:

To a solution of tert-butylN-[(3R)-1′-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(1.40 g, 2.19 mmol) in MeCN/AcOH (25.0 mL/25.0 mL) was added NBS (389.0mg, 2.19 mmol). The reaction mixture was stirred at 20° C. for 1 hour.The reaction mixture was then quenched with H₂O and concentrated underreduced pressure. The residue was triturated with H₂O (200.0 mL) andextracted with EtOAc (150.0 mL×2). The combined organic layers werewashed with brine (200.0 mL), dried over anhydrous Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure to give a residue.The residue was purified by flash silica gel chromatography (40 g, ethylacetate in petroleum ether from 0% to 35%) to give tert-butylN-[(3R)-1′-[5-bromo-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(1.25 g, 80% yield) as a yellow solid. LCMS m/z (M+H)⁺=717.0.

Step c:

A solution of tert-butylN-[(3R)-1′-[5-bromo-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(1.25 g, 1.74 mmol), trimethylboroxine (436.0 mg, 3.48 mmol),Pd(dppf)Cl₂ (254.0 mg, 348.0 umol) and K₂CO₃ (720.0 mg, 5.22 mmol) indioxane/H₂O (50.0 mL/5.0 mL) was stirred at 90° C. for 12 hours underN₂. The reaction mixture was poured into H₂O (150.0 mL) and extractedwith EtOAc (200.0 mL×2). The combined organic layers were washed withbrine (200.0 mL), dried over anhydrous Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure to give a residue. The residuewas purified by flash silica gel chromatography (40 g, ethyl acetate inpetroleum ether from 0% to 50%) to give tert-butylN-[(3R)-1′-[5-methyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(860.0 mg, 76% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 653.1 (M+H)⁺.

Step d:

A solution of tert-butylN-[(3R)-1′-[5-methyl-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(860.0 mg, 1.31 mmol) in HCl/MeOH (30.0 mL, 4 M) was stirred at 20° C.for 1 hour. The reaction mixture was concentrated under reduced pressureto give a solid. The solid was triturated with EtOAc and stirred for 0.5hour. The mixture was then filtered and the filter cake was lyophilized.(3R)-1′-[5-methyl-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride (589.3 mg, 89% yield) was obtained as an orange solid.LC-MS (ESI⁺) m/z: 469.1 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD): 8.05-8.07 (m,1H), 7.94-7.97 (m, 1H), 7.57-7.62 (m, 2H), 7.41-7.44 (m, 1H), 7.06-7.11(m, 1H), 7.00-7.03 (m, 1H), 4.75 (s, 1H), 4.08-4.12 (m, 2H), 3.92-3.94(m, 1H), 3.74-3.78 (m, 1H), 3.41-3.53 (m, 2H), 3.29-3.32 (m, 2H), 2.67(s, 3H), 2.33-2.41 (m, 3H), 2.10-2.18 (m, 2H), 1.98-2.06 (m, 1H).

Example 162: Synthesis of(3R)-1′-[5-methyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine

Step a:

A solution of tert-butylN-[(3R)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(702.0 mg, 1.1 mmol, Intermediate CC), piperidine (121.0 mg, 1.4 mmol,CAS #110-89-4), XantPhos-Pd-G4 (105.0 mg, 0.1 mmol, CAS #1621274-19-8)and Cs₂CO₃ (716.0 mg, 2.2 mmol) in PhMe (15 mL) was stirred at 110° C.for 12 hours under N₂. The reaction mixture was diluted with H₂O (80 mL)and extracted with EtOAc (80 mL×3). The combined organic layers werewashed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (20 g, EtOAc in Petroleum ether from 0%˜35%) to givetert-butylN-[(3R)-1′-[1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(160.0 mg, 0.3 mmol, 24.6% yield) as a yellow oil. LCMS (ESI⁺) m/z:590.2 (M+H)⁺.(3R)-1′-[5-methyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride was then synthesized via Steps b-d as described in Example161, where Step b was run at 0° C. instead of 25° C. for 1 hr.(3R)-1′-[5-methyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride (69.0 mg, 90% yield in Step d) was isolated as a brownsolid. LC-MS (ESI⁺) m/z: 420.1 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 7.56 (d,J=7.6 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.99 (d,J=8.4 Hz, 1H), 4.69 (s, 1H), 4.08 (d, J=12.4 Hz, 1H), 3.92-3.87 (m, 5H),3.53-3.40 (m, 2H), 2.65 (s, 3H), 2.34-2.28 (m, 1H), 2.14-1.93 (m, 3H),1.77 (s, 6H).

Example 163: Synthesis of6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

Step a:

A mixture of tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(600.0 mg, 951 μmol, Intermediate J), Zn(CN)₂ (272.0 mg, 1.9 mmol) and[(t-Bu₃P)₂]Pd (48.5 mg, 95.1 μmol) in DMF (30 mL) was stirred at 130° C.for 12 hours under N₂ atmosphere. The reaction mixture was diluted withethyl acetate (45 mL), washed with H₂O (35 mL×2) and brine (20 mL), thendried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to givea residue. The residue was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 40%) to afford tert-butylN-[(3S)-1′-[3-cyano-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(360.0 mg, 72% yield) as a yellow solid. LCMS (ESI⁺) m/z: 552.1 (M+Na)⁺.

Step b:

A mixture of tert-butylN-[(3S)-1′-[3-cyano-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(360 mg, 679 μmol) in MeOH (8.0 mL) and aq.NaOH (10%, 8.0 mL) wasstirred at 90° C. for 1 hour. The mixture was concentrated in vacuo togive a residue, which was diluted with H₂O (20 mL) and adjusted pH=4with 2N NaOH, then extracted with ethyl acetate (30 mL×3). The combinedorganic phases were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to afford6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxylicacid (360.0 mg, 97% yield) as a yellow solid. LCMS (ESI⁺) m/z: 549.1(M+H)⁺.

Step c:

A mixture of6-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxylicacid (360.0 mg, 656 μmol), ammonium 1H-1,2,3-benzotriazol-1-olate (149.0mg, 984 μmol) and EDCI (188 mg, 984 μmol) in DMF (15.0 mL) was stirredat 25° C. for 1 hour. The reaction mixture was diluted with ethylacetate (40 mL), then washed with H₂O (30 mL×3). The combined organicphase was washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (methanol in petroleum ether=0% to10%) to afford tert-butylN-[(3S)-1′-[3-carbamoyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(220.0 mg, 61% yield) as a yellow oil. LCMS (ESI⁺) m/z: 548.1 (M+H)⁺.

Step d:

To a mixture of tert-butylN-[(3S)-1′-[3-carbamoyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(220.0 mg, 401 μmol) in MeCN (10.0 mL) and AcOH (1.0 mL) was added NBS(106.0 mg, 601 μmol), the resulting mixture was stirred at 25° C. for 12hours. The reaction mixture was concentrated in vacuo to give a residue,which was dissolved in ethyl acetate (25 mL), then washed with sat.NaHCO₃ (15 mL×2). The organic phase was washed with brine (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give aresidue, which was purified by silica gel chromatography (methanol indichloromethane=0% to 10%) to afford tert-butylN-[(3S)-1′-{5-bromo-3-carbamoyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(210 mg, 97% yield) as a yellow solid. LCMS (ESI⁺) m/z: 543.0 and 544.0(M+H)⁺.

Step e:

A mixture of tert-butylN-[(3S)-1′-{5-bromo-3-carbamoyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(210.0 mg, 387 μmol), TFAA (108.0 μL, 774 μmol) and TEA (160.0 μL, 1.2mmol) in DCM (10 mL) was stirred at 25° C. for 12 hours under N₂atmosphere. The reaction mixture was diluted with sat.NaHCO₃ (25 mL),then extracted with DCM (30 mL×3). The combined organic phases werewashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue, which was purified by silicagel chromatography (ethyl acetate in petroleum ether=0% to 35%) toafford tert-butylN-[(3S)-1′-{5-bromo-3-cyano-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100 mg, 50% yield) as a yellow solid. LCMS (ESI⁺) m/z: 546.0 (M+Na)⁺.

Step f:

A mixture of tert-butylN-[(3S)-1′-{5-bromo-3-cyano-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100.0 mg, 190 μmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (71.5 mg,570 μmol), Pd(dppf)Cl₂ (13.9 mg, 19.0 μmol) and K₂CO₃ (52.4 mg, 380μmol) in 1,4-dioxane (10.0 mL) and H₂O (1.0 mL) was stirred at 90° C.for 12 hours under N₂ atmosphere. The reaction mixture was concentratedin vacuo to give a residue, which was purified by silica gelchromatography (ethyl acetate in petroleum ether=0% to 30%) to affordtert-butylN-[(3S)-1′-{3-cyano-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(35.0 mg, 40% yield) as a yellow oil. LCMS (ESI⁺) m/z: 404.0 (M+H-Boc)⁺.

Step g:

A mixture of tert-butylN-[(3S)-1′-[3-cyano-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(35.0 mg, 64.3 μmol) in TFA (1.0 mL) was stirred at 25° C. for 2 hours.The reaction mixture was concentrated in vacuo to give a residue, whichwas dissolved in MeOH (5 mL) and adjusted pH=8 with solid Na₂CO₃. Themixture was filtered and concentrated in vacuo to give a residue, whichwas purified by prep-HPLC (NH₃.H₂O) to afford6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile(2.8 mg, 12% yield) as a yellow solid. LCMS (ESI⁺) m/z: 343.1(M+H-NH₂)⁺. ¹HNMR (400 MHz, Methanol-d₄): 7.45-7.43 (m, 1H), 7.32-7.24(m, 3H), 4.15 (s, 1H), 3.74-3.69 (m, 2H), 3.26-3.15 (m, 3H), 2.92 (d,J=16.0 Hz, 1H), 2.70 (s, 3H), 2.07-1.96 (m, 2H), 1.70-1.59 (m, 2H).

Example 164: Synthesis of(3S)-1′-{5-[(2S)-2-phenylpyrrolidin-1-yl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of (S)-tert-butyl(1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(150.0 mg, 326 μmol, Intermediate CZ), (2R)-2-phenylpyrrolidine (47.9mg, 326 μmol, CAS #56523-47-8), Cs₂CO₃ (318.0 mg, 978 μmol),RuPhos-Pd-G4 (27.7 mg, 32.6 μmol) and RuPhos (30.4 mg, 65.2 μmol) intoluene (6.00 mL) was stirred at 100° C. for 12 hours under N₂atmosphere. Then H₂O (10 mL) was added and the mixture was extractedwith ethyl acetate (15 mL×3). The combined organic layers were washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (ethyl acetate/petroleum ether=0/100 to 25/100) toafford tert-butylN-[(3S)-1′-{5-[(2R)-2-phenylpyrrolidin-1-yl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(79.0 mg, 46% yield) as a green oil. LCMS (ESI⁺) m/z: 526.2 (M+H)⁺.

Step b:

The compound of tert-butylN-[(3S)-1′-{5-[(2R)-2-phenylpyrrolidin-1-yl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(79.0 mg, 150 μmol) was added into HCl/dioxane (6.00 mL, 4 M). Themixture was stirred at 25° C. for 0.5 h. The mixture was diluted withH₂O (20 mL) and EtOAc (20 mL), then the partitioned layers wereseparated. The aqueous phase was extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine (30 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by prep-HPLC (NH₃.H₂O) to afford(3S)-1′-{5-[(2S)-2-phenylpyrrolidin-1-yl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(21.0 mg, 33% yield) as a yellow solid. LCMS (ESI⁺) m/z: 426.1 (M+H)⁺.¹HNMR (400 MHz, DMSO-d₆) δ=7.80 (s, 1H), 7.37 (s, 1H), 7.33-7.25 (m,3H), 7.21-7.14 (m, 6H), 4.94-4.92 (m, 1H), 3.54-3.47 (m, 3H), 3.46-3.43(m, 2H), 2.98 (m, 1H), 2.91-2.78 (m, 2H), 2.56 (m, 1H), 2.44-2.31 (m,1H), 2.00-1.88 (m, 2H), 1.82-1.60 (m, 3H), 1.45 (m, 1H), 1.07 (m, 1H).

Example 165: Synthesis of(3S)-1′-{5-[(2S)-2-phenylpyrrolidin-1-yl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

(3S)-1′-{5-[(2S)-2-phenylpyrrolidin-1-yl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminewas synthesized as described in Example 164, using(2S)-2-phenylpyrrolidine (CAS #59347-91-0) in the coupling in Step 1.Characterization data for(3S)-1′-{5-[(2S)-2-phenylpyrrolidin-1-yl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine:LCMS (ESI⁺) m/z: 426.3 (M+H)[; ¹HNMR (400 MHz, CD₃CN) δ=7.68 (m, 1H),7.38 (m, 1H), 7.32-7.26 (m, 3H), 7.25-7.14 (m, 6H), 4.93 (m, 1H), 3.86(s, 1H), 3.85-3.69 (m, 3H), 3.59-3.48 (m, 1H), 3.01 (m, 1H), 2.98-2.84(m, 2H), 2.41-2.40 (m, 1H), 2.48-2.36 (m, 1H), 2.04-1.96 (m, 2H),1.88-1.76 (m, 2H), 1.68 (m, 1H), 1.49 (m, 1H), 1.21-1.11 (m, 1H).

Example 166: Synthesis of(S)-1′-(5-((R)-2-phenylpiperidin-1-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

(S)-1′-(5-((R)-2-phenylpiperidin-1-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminewas synthesized as described in Example 164, using(2R)-2-phenylpiperidine (CAS #58613-54-0), in the coupling in Step 1.Characterization data for(S)-1′-(5-((R)-2-phenylpiperidin-1-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LCMS (ESI⁺) m/z: 440.2 (M+H)⁺; ¹HNMR (400 MHz, CD₃CN) δ=7.79 (s, 1H),7.69 (s, 1H), 7.35-7.24 (m, 5H), 7.19 (s, 4H), 5.10-4.98 (m, 1H),3.94-3.79 (m, 3H), 3.74-3.63 (m, 1H), 3.34 (m, 1H), 3.09-2.93 (m, 3H),2.65 (m, 1H), 2.07-2.01 (m, 2H), 1.85-1.69 (m, 4H), 1.62-1.50 (m, 3H),1.21 (m, 1H).

Example 167: Synthesis of(3S)-1′-[3-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

(3S)-1′-{3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(60.0 mg, 130 μmol, Intermediate DB),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(32.5 mg, 155.0 μmol), Pd(dppf)Cl₂ (9.5 mg, 13.0 μmol) and Cs₂CO₃ (84.7mg, 260.0 μmol) were placed into the solvent of dioxane (15 mL) and H₂O(1.5 mL). The reaction mixture was evacuated and refilled for 3 timesusing N₂. The reaction mixture was stirred at 90° C. for 12 hours. Thereaction mixture was concentrated and H₂O (20 mL) was added, then themixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byprep-HPLC (HCl) to afford(3S)-1′-[3-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(5.0 mg, 9.2% yield, HCl salt) as a yellow solid. LCMS (ESI⁺) m/z: 417.1(M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 7.53˜7.56 (m, 1H), 7.30˜7.44 (m, 4H),4.47 (s, 1H), 4.40˜4.42 (m, 2H), 3.97˜4.00 (m, 2H), 3.63˜3.76 (m, 2H),2.69˜2.73 (m, 2H), 2.68 (s, 3H), 1.95-2.63 (m, 2H), 1.81˜1.86 (m, 1H),1.69˜1.73 (m, 1H).

Example 168: Synthesis of(3S)-1′-[5-(cyclopentylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To the reaction mixture of bromocyclopentane (163.0 mg, 1.1 mmol, CAS#137-43-9) and TEA (228 μL, 1.7 mmol) in DMF (2 mL) was added tert-butylN-[(3S)-1′-[5-(sodiosulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 0.3 mmol, Intermediate DE). The reaction mixture was stirredat 25° C. for 1 hour. The combined reaction mixture was quenched withwater (20 mL), then extracted with EtOAc (50 mL×2). The organic layerswere washed with water (50 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by prep-TLC (Petroleumether/EtOAc=4/1) to give tert-butylN-[(3S)-1′-[5-(cyclopentylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(55.0 mg, 33% yield) as a white solid. LCMS (ESI⁺) m/z: 481.0 (M+H)⁺.

Step b:

The mixture of tert-butylN-[(3S)-1′-[5-(cyclopentylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 0.1 mmol) in HCl/MeOH (2 mL, 4 M) was stirred at 25° C. for0.5 hour. The combined reaction mixture was concentrated to give aresidue. The residue was purified by prep-HPLC (HCl condition) to give(3S)-1′-[5-(cyclopentylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (28.6 mg, 75% yield) as a yellow solid. LCMS (ESI⁺) m/z:381.0 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 8.17 (s, 1H), 7.51(d, J=7.6 Hz, 1H), 7.41-7.33 (m, 3H), 4.40 (s, 1H), 4.33 (d, J=14 Hz,1H), 4.19 (d, J=14.4 Hz, 1H), 3.76-3.73 (m, 1H), 3.38-3.33 (m, 2H), 3.19(s, 2H), 2.05-1.62 (m, 12H).

Example 169: Synthesis of(3S)-1′-{imidazo[1,2-a]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

(3S)-1,3-Dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(240.0 mg, 872 μmol, Intermediate I) was dissolved in MeOH (2.00 mL).The mixture was then adjusted to pH=9-10 with solid Na₂CO₃, then themixture was filtered. Next, 6-chloroimidazo[1,2-a]pyrazine (121.0 mg,792 μmol, CAS #76537-23-0) was added into the filtrate. The mixture wasconcentrated to give a residue. NMP (2 drops) was added to the residue,then the mixture was stirred at 150° C. for 2 h. On completion, themixture was cooled to rt and was purified by prep-HPLC (NH₃.H₂O) toafford(3S)-1′-{imidazo[1,2-a]pyrazin-6-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(27.2 mg, 11% yield) as a gray solid. LCMS (ESI⁺) m/z: 320.1 (M+H)⁺;¹HNMR (400 MHz, Methanol-d₄) δ=8.77 (m, 1H), 7.94-7.84 (m, 2H), 7.69 (m,1H), 7.47-7.36 (m, 1H), 7.23-7.16 (m, 3H), 3.99 (s, 1H), 3.93-3.83 (m,2H), 3.15-3.11 (m, 4H), 2.79 (m, 1H), 2.10-1.83 (m, 2H), 1.65 (m, 1H),1.56-1.46 (m, 1H).

Example 170: Synthesis of(3S)-1′-[5-(ethylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To the reaction mixture of iodoethane (179.0 mg, 1.2 mmol) and TEA (190μL, 1.4 mmol) in DMF (2 mL) was added tert-butylN-[(3S)-1′-[5-(sodiosulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(100.0 mg, 0.2 mmol, Intermediate DE). The reaction mixture was stirredat 25° C. for 0.5 hour. The combined reaction mixture was quenched withwater (20 mL), then extracted with EtOAc (50 mL×2). The organic layerswere washed with water (50 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by prep-TLC (petroleumether/EtOAc=4/1) to afford tert-butylN-[(3S)-1′-[5-(ethylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(76.0 mg) as a light yellow solid. LCMS (ESI⁺) m/z: 441.1 (M+H)⁺.

Step b:

The mixture of tert-butylN-[(3S)-1′-[5-(ethylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(76.0 mg, 0.172 mmol) in HCl/MeOH (2 mL, 4 M) was stirred at 25° C. for0.5 hour. The reaction mixture was then concentrated to give a residue.The residue was purified by prep-HPLC (neutral condition) to give(3S)-1′-[5-(ethylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(16.0 mg, 27% yield) as a yellow oil. LCMS (ESI⁺) m/z: 340.9 (M+H)⁺;¹HNMR (400 MHz, CD₃OD) δ 8.15 (s, 1H), 8.05 (s, 1H), 7.38-7.35 (m, 1H),7.21-7.18 (m, 3H), 4.19-4.13 (m, 2H), 3.94 (s, 1H), 3.23-3.11 (m, 3H),2.98 (q, J=7.2 Hz, 2H), 2.78 (d, J=15.6 Hz, 1H), 1.85-1.76 (m, 2H),1.60-1.44 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).

Example 171: Synthesis of(3S)-1′-[5-(cyclopropylmethoxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

The mixture of tert-butylN-[(3S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 0.4 mmol, Intermediate CZ), Cs₂CO₃ (285.0 mg, 0.9 mmol), CuI(8.3 mg, 0.04 mmol) and Me₄-Phenanthroline (20.5 mg, 0.09 mmol, CAS#1660-93-1) in cyclopropylmethanol (3 mL) was bubbled with N₂ for 5 min;then stirred under microwave irradiation at 100° C. for 8 hours. Thereaction mixture was then diluted with H₂O (20 mL), and extracted withEtOAc (30 mL×2). The organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash silica gelchromatography (12 g column, EtOAc in petroleum ether from 0%˜15%) togive tert-butylN-[(3S)-1′-[5-(cyclopropylmethoxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(148.0 mg, 75% yield) as a yellow oil.

Step b:

To the reaction mixture of tert-butylN-[(3S)-1′-[5-(cyclopropylmethoxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(90.0 mg, 0.2 mmol) in DCM (4 mL) was added TFA (0.4 mL). The reactionmixture was stirred at 25° C. for 1 hour. The reaction mixture was thenadjusted to pH=8-9 with solid Na₂CO₃, and filtered. The filtrate wasconcentrated to give a residue which was purified by prep-HPLC (basiccondition) to give(3S)-1′-[5-(cyclopropylmethoxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(17.8 mg, 25% yield) as a yellow oil. LCMS (ESI⁺) m/z: 351.1 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.65 (s, 1H), 7.34 (d, J=5.2 Hz,1H), 7.24-7.21 (m, 3H), 4.06 (d, J=6.8 Hz, 2H), 4.00 (s, 1H), 3.94-3.89(m, 2H), 3.12-3.03 (m, 3H), 2.71 (d, J=16.0 Hz, 1H), 1.90-1.80 (m, 2H),1.61-1.60 (m, 1H), 1.41-1.26 (m, 2H), 0.64-0.60 (m, 2H), 0.37-0.34 (m,2H).

Examples 172, 173, 174, 175 Syntheses of(1S,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-amine(172),(1R,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-amine(173),(1R,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-amine(174), and(1S,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-amine(175)

Step a:

4-[1-(Oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1(580.0 mg, 1.1 mmol, Intermediate DF) was added into HCl/MeOH (15.00 mL,4 M). The mixture was stirred at 25° C. for 1 hour. The mixture was thenconcentrated to give a residue. The residue was triturated withEtOAC:MeOH=10:1, where a yellow solid was formed, which was collected byfiltration. The solid was then dissolved in MeOH (25 mL) and the mixturewas adjusted to pH=9-10 with TEA. The mixture was concentrated to give4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1(450.0 mg, 93% crude yield) as a yellow solid. LCMS (ESI⁺) m/z: 449.0(M+H)⁺.

Step b:

To a solution of4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one(250.0 mg, 557 μmol) and Ti(OEt)₄ (1.14 mL, 5.6 mmol) in 2-Me-THF (3.00mL) was added (R)-2-methylpropane-2-sulfinamide (269.0 mg, 2.2 mmol).The reaction mixture was stirred at 95° C. for 72 hours under N₂. Themixture was then diluted with EtOAc (100 mL) and H₂O (20 mL) was added,where white solid formed. The mixture was filtered and the partitionedlayers of the filtrate were separated. The aqueous phase was extractedwith ethyl acetate (50 mL×2). The combined organic layers were washedwith H₂O (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give(R)-2-methyl-N-{4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-ylidene}propane-2-sulfinamide(300.0 mg, 98% crude yield) as a yellow oil. LCMS (ESI⁺) m/z: 552.1(M+H)⁺.

Step c:

(R)-2-methyl-N-{4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-ylidene}propane-2-sulfinamide(300.0 mg, 543 μmol) was dissolved in 2-Me-THF (10.00 mL). Then NaBH₄(40.8 mg, 1.1 mmol) was added at −20° C. and the mixture was allowed towarm to 25° C. and stirred for 2 hours. The reaction was quenched withH₂O (5 mL), then the mixture was extracted with ethyl acetate (10 mL×3).The combined organic layers were washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give(R)—N-(4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(300 mg, 100% yield, crude) as a yellow oil. LCMS (ESI⁺) m/z: 554.1(M+H)⁺.

Step d:

(R)—N-(4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(300.0 mg, 541 μmol) was added into HCl/MeOH (5 mL, 4M). The mixture wasstirred at 25° C. for 0.5 hour. Then the mixture was concentrated togive a residue which was next dissolved in MeOH (5 mL). The mixture wasadjusted to pH=9-10 with TEA. The mixture was then concentrated to give4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-amine(243 mg, 100% yield, crude) as a yellow solid. LCMS (ESI⁺) m/z: 450.0(M+H)⁺.

Step e:

4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-amine(243.0 mg, 540 μmol) and TEA (149 μL, 1.08 mmol) were dissolved in DCM(13 ml). Then (Boc)₂O (135 μL, 594 μmol) in DCM (2 mL) was added and themixture was stirred at 25° C. for 2 hours. The mixture was then washedwith H₂O (10 mL×2), brine (10 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by pre-HPLC(petroleum ether:ethyl acetate=1:2) to afford tert-butyl(4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(105 mg, 35% yield) as a yellow solid LCMS (ESI⁺) m/z: 550.1 (M+H)⁺.

Step f:

Tert-butyl(4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(105.0 mg, 191 μmol) was separated by Chiral-SFC (DAICEL CHIRALPAK AD(250 mm×30 mm, 10 u m), mobile phase: 40% of IPA (0.1% NH₃.H₂O) in CO₂.Flow rate: 80 mL/min.) to afford tert-butyl((1R,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamateand tert-butyl((1S,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate,as well as a mixture of tert-butyl((1R,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-1′-yl)carbamateand tert-butyl((1S,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-1′-yl)carbamate.Absolute stereochemical configuration was assigned randomly for all fourisomers. tert-butyl((1R,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(12 mg) was further purified by Chiral-SFC (Column: DAICEL CHIRALPAK AD(250 mm×30 mm, 10 um). Mobile phase: 40% of IPA (0.1% NH₃.H₂O) in CO₂.Flow rate: 70 mL/min.) to afford the product of tert-butyl((1R,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(10.0 mg, 84% yield) as a yellow solid. LCMS (ESI+) m/z: 550.1 (M+H)⁺.The product of tert-butyl((1S,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(32.0 mg, 31% yield) was obtained as a yellow solid. LC-MS (ESI⁺) m/z:550.1 (M+H)⁺.

The mixture (50 mg) of tert-butyl((1R,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-1′-yl)carbamateand tert-butyl((1S,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-1′-yl)carbamatewas separated by Chiral-SFC (Column: DAICEL CHIRALPAK IG (250 mm×30 mm,10 um), Mobile phase: 55% of EtOH (0.1% NH₃.H₂O) in CO₂. Flow rate: 80mL/min) to afford of tert-butyl((1R,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-1′-yl)carbamate(42.0 mg, 60% yield. LCMS (ESI⁺) m/z: 550.1 (M+H)⁺) and tert-butyl((1S,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-1′-yl)carbamate(8.0 mg, 20% yield, LC-MS (ESI⁺) m/z: 550.1 (M+H)⁺) as yellow solids.

Step g:

Tert-butyl((1S,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(10.0 mg, 18.1 μmol) was added into HCl/MeOH (5 mL, 4 M) and the mixturewas stirred at 25° C. for 1 hour. The mixture was then concentrated togive a residue. The residue was lyophilized to afford(1S,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-aminehydrochloride (7.60 mg, HCl salt, 86% yield) as a brown solid. LCMS(ESI⁺) m/z: 450.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.80 (s, 1H),7.97-8.06 (m, 2H), 7.42˜7.51 (m, 2H), 7.24˜7.31 (m, 3H), 6.94 (s, 1H),4.39 (s, 1H), 4.06˜4.10 (m, 2H), 3.14˜3.20 (m, 2H), 2.90˜3.04 (m, 2H),2.67˜2.86 m, 2H), 2.49-2.60 (m, 1H), 2.32˜2.39 (m, 1H), 2.20˜2.27 (m,2H), 1.77˜1.92 (m, 2H). SFC: e.e. =99.6%, R_(t)=4.217 min. Column:Chiralpak AS-3 100×4.6 mm I.D., 3 m. Mobile phase: A: CO₂. B: ethanol(0.05% DEA). Gradient: from 5% to 40% of B in 4 min and hold 40% for 2.5min, then 5% of B for 1.5 min. Flow rate: 2.8 mL/min. Column temp: 35°C. Absolute stereochemistry was randomly assigned.

Step h:

Tert-butyl((1R,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(42 mg, 76.4 μmol) was added into HCl/MeOH (5 mL, 4 M) and the mixturewas stirred at 25° C. for 1 hour. The mixture was then concentrated togive a residue. The residue was lyophilized to afford(1R,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-aminehydrochloride (36.4 mg, HCl salt, 98% yield) as a brown solid. LCMS(ESI⁺) m/z: 450.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.89 (s, 1H),8.09˜8.17 (m, 2H), 7.55˜7.60 (m, 2H), 7.35˜7.41 (m, 3H), 6.96 (s, 1H),4.49 (s, 1H), 4.18˜4.22 (m, 2H), 3.27˜3.32 (m, 2H), 3.20˜3.25 (m, 1H),3.09˜3.16 (m, 1H), 2.91˜2.96 m, 1H), 2.71˜2.81 (m, 1H), 2.51˜2.57 (m,1H), 2.31˜2.38 (m, 3H), 1.94˜2.05 (m, 2H). SFC: e.e. =99.1%, R_(t)=4.552min. Column: Chiralpak AS-3 100×4.6 mm I.D., 3 m. Mobile phase: A: CO₂.B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 4 min and hold40% for 2.5 min, then 5% of B for 1.5 min. Flow rate: 2.8 mL/min. Columntemp: 35° C. Absolute stereochemistry was randomly assigned.

Step i:

Tert-butyl((1S,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(8 mg, 14.5 μmol) was added into HCl/MeOH (5 mL, 4 M) and the mixturewas stirred at 25° C. for 1 hour. The mixture was then concentrated togive a residue. The residue was lyophilized to afford(1R,1′R)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-aminehydrochloride (6.90 mg, HCl salt, 98% yield) as a brown solid. LC-MS(ESI⁺) m/z: 450.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.89 (s, 1H),8.08˜8.17 (m, 2H), 7.55˜7.60 (m, 2H), 7.35˜7.42 (m, 3H), 6.96 (s, 1H),4.48 (s, 1H), 4.17˜4.21 (m, 2H), 3.26˜3.32 (m, 2H), 3.19˜3.24 (m, 1H),3.08˜3.15 (m, 1H), 2.90˜2.95 m, 1H), 2.74˜2.81 (m, 1H), 2.51˜2.56 (m,1H), 2.31˜2.36 (m, 3H), 1.95˜2.06 (m, 2H). SFC: e.e. =100.0%,R_(t)=4.552 min. Column: Chiralpak AS-3 100×4.6 mm I.D., 3 m. Mobilephase: A: CO₂. B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in4 min and hold 40% for 2.5 min, then 5% of B for 1.5 min. Flow rate: 2.8mL/min. Column temp: 35° C. Absolute stereochemistry was randomlyassigned.

Step j:

Tert-butyl((1S,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-yl)carbamate(32.0 mg, 58.2 μmol) was added into HCl/MeOH (5.00 mL, 4 M) and themixture was stirred at 25° C. for 1 hour. The mixture was thenconcentrated to give a residue. The residue was lyophilized to afford(1S,1′S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohex[3]ene-1,2′-inden]-1′-aminehydrochloride (26.9 mg, HCl salt, 95% yield) as a brown solid. LCMS(ESI⁺) m/z: 450.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.79 (s, 1H),7.97˜8.05 (m, 2H), 7.42˜7.51 (m, 2H), 7.24˜7.31 (m, 3H), 6.94 (s, 1H),4.39 (s, 1H), 4.06˜4.10 (m, 2H), 3.16˜3.20 (m, 2H), 2.90˜3.04 (m, 2H),2.67˜2.86 m, 2H), 2.49-2.55 (m, 1H), 2.32˜2.39 (m, 1H), 2.20˜2.27 (m,2H), 1.77˜1.92 (m, 2H). SFC: e.e. =98.6%, R_(t)=4.217 min. Column:Chiralpak AS-3 100×4.6 mm I.D., 3 m. Mobile phase: A: CO₂. B: ethanol(0.05% DEA). Gradient: from 5% to 40% of B in 4 min and hold 40% for 2.5min, then 5% of B for 1.5 min. Flow rate: 2.8 mL/min. Column temp: 35°C. Absolute stereochemistry was randomly assigned.

Example 185: Synthesis of(S)-1′-(5-((tetrahydro-2H-pyran-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

To the reaction mixture of 4-bromooxane (227.0 mg, 1.4 mmol, CAS#25637-16-5) and TEA (287 μL, 2.1 mmol) in DMF (2.00 mL) was addedsodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate(150.0 mg, 0.3 mmol, Intermediate DE) and the reaction mixture wasstirred at 25° C. for 1 hour. The combined reaction mixture was thenquenched with water (20 mL), and extracted with EtOAc (50 mL×2). Theorganic layers were washed with water (50 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by prep-TLC(petroleum ether/EtOAc=4/1) to give (S)-tert-butyl(1′-(5-((tetrahydro-2H-pyran-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(28.0 mg, 20% yield) as a light yellow solid. LCMS (ESI⁺) m/z: 497.1(M+H)⁺.

Step b:

The mixture of (S)-tert-butyl(1′-(5-((tetrahydro-2H-pyran-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(16 mg, 0.03 mmol) in HCl/MeOH (2 mL, 4 M) was stirred at 25° C. for 0.5hour. The reaction mixture was then concentrated to give a residue. Theresidue was dissolved in MeOH (5 mL), and the reaction mixture wasadjusted to pH=8-9 with solid Na₂CO₃. The mixture was filtered, and thefiltrate was concentrated to give a residue. The residue was purified byprep-HPLC (neutral condition) to give(S)-1′-(5-((tetrahydro-2H-pyran-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(13.2 mg, 0.03 mmol, combined product) as a yellow solid. LCMS (ESI⁺)m/z: 397.1 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 1H), 8.10 (s, 1H),7.37-7.35 (m, 1H), 7.23-7.18 (m, 3H), 4.22-4.18 (m, 1H), 3.94-3.91 (m,3H), 3.49-3.42 (m, 3H), 3.22-3.12 (m, 3H), 2.78 (d, J=16.0 Hz, 1H),1.92-1.44 (m, 8H).

Example 186: Synthesis of(3S)-1′-[3-(4,4-difluoropiperidin-1-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

(3S)-1′-[3-(4,4-difluoropiperidin-1-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminewas synthesized as described for Example 152, coupling tert-butyl((1S)-1′-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(Intermediate J) with 4,4-difluoropiperidine (CAS #21987-29-1) in Stepa. Characterization of final compound: LCMS (ESI⁺) m/z: 454.1 (M+H)⁺;¹HNMR (400 MHz, Methanol-d₄) δ 7.53 (m, 1H), 7.44-7.30 (m, 3H),4.48-4.41 (m, 1H), 4.01-3.93 (m, 4H), 3.93-3.75 (m, 2H), 3.30-3.21 (m,2H), 3.19 (s, 2H), 2.68-2.59 (m, 3H), 2.25-1.60 (m, 8H).

Example 187: Synthesis of(3R)-1′-{5-[(2-amino-3-chloropyridin-4-yl)oxy]pyrazin-2-yl}-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine

Step a:

A mixture of tert-butylN-[(3R)-1′-(5-bromopyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(680.0 mg, 1.5 mmol, Intermediate CL), KOH (247.0 mg, 4.4 mmol),t-BuXPhos (124.0 mg, 294 μmol) and Pd₂(dba)₃ (134.0 mg, 147 μmol) in1,4-dioxane (8.0 mL) and H₂O (8.0 mL) was stirred at 100° C. for 3 hoursunder N₂ atmosphere. The reaction mixture was cooled to 0° C., then wasacidified to pH=5 with 1 N HCl, and extracted with ethyl acetate (20mL×3). The organic phases were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue,which was purified by silica gel chromatography (Petroleum ether inEthyl acetate=0% to 90%) to afford tert-butylN-[(3R)-1′-(5-hydroxypyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(210.0 mg, 36% yield) as a yellow solid. LCMS (ESI⁺) m/z: 399.0 (M+H)⁺.

Step b:

A mixture of tert-butylN-[(3R)-1′-(5-hydroxypyrazin-2-yl)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 501 μmol), 2,3,4-trichloropyridine (109.0 mg, 601 μmol, CAS#55934-02-6) and Cs₂CO₃ (326.0 mg, 1.0 mmol) in DMF (15.0 mL) wasstirred at 80° C. for 2.5 hours. The reaction mixture was diluted withethyl acetate (30 mL), then washed with H₂O (20 mL×2). The organic phasewas washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (ethyl acetate in petroleum ether=0% to 40%)to afford tert-butylN-[(3R)-1′-{5-[(2,3-dichloropyridin-4-yl)oxy]pyrazin-2-yl}-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(150.0 mg, 55% yield) as a yellow oil. LCMS (ESI⁺) m/z: 544.0 (M+H)⁺.

Step c:

A mixture of tert-butylN-[(3R)-1′-{5-[(2,3-dichloropyridin-4-yl)oxy]pyrazin-2-yl}-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(150.0 mg, 275 μmol), diphenylmethanimine (99.6 mg, 550 μmol), BINAP(34.2 mg, 55.0 μmol), Cs₂CO₃ (179.0 mg, 550 μmol) and Pd₂(dba)₃ (25.1mg, 27.5 μmol) in toluene (15.0 mL) was stirred at 100° C. for 12 hoursunder N₂ atmosphere. The reaction mixture was concentrated in vacuo togive a residue, which was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 40%) to afford tert-butylN-[(3R)-1′-[5-({3-chloro-2-[(diphenylmethylidene)amino]pyridin-4-yl}oxy)pyrazin-2-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 63% yield) as a yellow oil. LCMS (ESI⁺) m/z: 689.1 (M+H)⁺.

Step d:

A mixture of tert-butylN-[(3R)-1′-[5-({3-chloro-2-[(diphenylmethylidene)amino]pyridin-4-yl}oxy)pyrazin-2-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 174 μmol) in HCl/MeOH (2M, 5.0 mL) was stirred at 25° C. for3 hours. The reaction mixture was concentrated in vacuo to give aresidue, which was dissolved in MeOH (5 mL) and adjusted pH=8 with solidNa₂CO₃. The mixture was filtered and concentrated in vacuo to give aresidue, which was purified by prep-HPLC (NH₃.H₂O) to afford(3R)-1′-{5-[(2-amino-3-chloropyridin-4-yl)oxy]pyrazin-2-yl}-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine(39.3 mg, 53% yield) as a white solid. LCMS (ESI⁺) m/z: 425.1 (M+H)⁺;¹HNMR (400 MHz, Methanol-d₄): 8.05 (d, J=1.2 Hz, 1H), 7.96 (d, J=1.2 Hz,1H), 7.77 (d, J=5.6 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.20 (t, J=7.6 Hz,1H), 6.92 (t, J=7.6 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.22 (d, J=5.6 Hz,1H), 4.36-4.28 (m, 1H), 4.24-4.18 (m, 1H), 4.12 (s, 1H), 3.49-3.39 (m,2H), 2.03-1.81 (m, 4H).

Examples 188 & 189: Syntheses of (1s, 1′R,4S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-amineand(1s,3′S,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine

Step a:

4-[1-(Oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3-en-3′-one(500.0 mg, 938 μmol, Intermediate DF) was dissolved in MeOH (50 mL).Then 10% Pd/C (50 mg, wet) was added and the reaction mixture wasevacuated and refilled 3 times using H₂ gas. The reaction mixture wasstirred at 25° C. for 72 hours under H₂ (15 psi). The reaction mixturewas then filtered through a pad of celite and washed with MeOH (20 mL).The filtrate was concentrated to give4-[1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(501 mg, 100% yield, crude) as a yellow oil. LCMS (ESI⁺) m/z: 535.0(M+H)⁺.

Step b:

4-[1-(Oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(501.0 mg, 937 μmol) was added into HCl/MeOH (4 mL, 4M). The mixture wasstirred at 25° C. for 1 h. The mixture was then concentrated andpurified by prep-HPLC (HCl) to give(1s,4s)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(HCl salt) and(1r,4r)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(HCl salt). After lyophilization,(1s,4s)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(HCl salt) was dissolved in MeOH (5 mL). The mixture was adjusted topH=9-10 with TEA and concentrated to give(1s,4s)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(free base) (50 mg, 12% yield) as a yellow solid. LCMS (ESI⁺) m/z: 451.0(M+H)⁺. ¹HNMR (400 MHz, CDCl₃): δ 10.57 (s, 1H), 8.46 (s, 1H), 8.01˜8.03(m, 1H), 7.66˜7.68 (m, 1H), 7.58˜7.62 (m, 1H), 7.50˜7.55 (m, 1H),7.28˜7.37 (m, 2H), 6.90˜6.93 (m, 1H), 4.08˜4.12 (m, 2H), 2.97˜3.07 (m,5H), 2.47˜2.57 (m, 2H), 2.12˜2.19 (m, 2H), 1.99˜2.03 (m, 2H), 1.84˜1.89(m, 2H), 1.60˜1.68 (m, 2H), 1.50˜1.54 (m, 2H).(1r,4r)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(HCl salt) was also dissolved in MeOH (5 mL). The mixture was adjustedto pH=9-10 with TEA and concentrated to give(1r,4r)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one((80 mg, 19% yield). LCMS (ESI⁺) m/z: 451.0 (M+H)⁺. ¹HNMR (400 MHz,CDCl₃): δ 10.27 (s, 1H), 8.39 (s, 1H), 8.02˜8.04 (m, 1H), 7.72˜7.75 (m,1H), 7.61˜7.64 (m, 1H), 7.53˜7.58 (m, 1H), 7.38˜7.41 (m, 1H), 7.31˜7.35(m, 1H), 6.90˜6.94 (m, 1H), 4.10˜4.13 (m, 2H), 2.98˜3.10 (m, 5H),2.12˜2.18 (m, 2H), 2.02˜2.07 (m, 2H), 1.82˜1.98 (m, 4H), 1.55˜1.7 (m,2H).

Step c:

To a solution of(1s,4s)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(80 mg, 177 μmol) and Ti(OEt)₄ (362 μL, 1.76 mmol, CAS #3087-36-3) in2-Me-THF (1 mL) was added (R)-2-methylpropane-2-sulfinamide (85.8 mg,708 μmol, CAS #196929-78-9). The reaction mixture was stirred at 95° C.for 72 h under N₂. The mixture was then diluted with EtOAc (30 mL) andH₂O (20 mL) was added, where lot of white solid formed. The mixture wasfiltered and the filtrate was extracted with ethyl acetate (10 mL×2).The combined organic layers were washed with H₂O (30 mL), brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give(R)-2-methyl-N-[(1S,4S)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-ylidene]propane-2-sulfinamide(90.0 mg, 92% yield, crude) as a yellow oil. LCMS (ESI⁺) m/z: 554.1(M+H)⁺.

Step d:

(R)-2-methyl-N-[(1s,4s)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1(90.0 mg, 162 μmol) was dissolved in 2-MeTHF (10 mL). Then NaBH₄ (12.2mg, 324 μmol) was added at −20° C. The mixture was then warmed to 25° C.and stirred for 2 hours. The reaction was quenched with H₂O (10 mL) andthe mixture was extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give (R)—N-((1s,4s)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(90.0 mg, 100% yield, crude) as a yellow oil. LCMS (ESI⁺) m/z: 578.1(M+Na)⁺.

Step e:

(R)—N-((1s,4s)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(90 mg, 161 μmol) was added into HCl/MeOH (5 mL, 4M). The mixture wasstirred at 25° C. for 0.5 h. The mixture was then concentrated to give aresidue which was dissolved in MeOH (5 mL). The mixture was adjusted topH=9-10 by with TEA. The mixture was then concentrated to give (1s,4s)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-amine(72.0 mg, 99% yield, crude) as a yellow solid. LCMS (ESI⁺) m/z: 452.0(M+H)⁺.

Step f:

(1s,4s)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-amine(72 mg, 159 μmol) and TEA (43.9 μL, 318 μmol) were dissolved in DCM (8ml). Then (Boc)₂O (39.8 μL, 174 μmol) in DCM (2 mL) was added. Themixture was stirred at 25° C. for 2 hours. The mixture was then washedwith H₂O (10 mL×2), brine (10 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by pre-TLC(petroleum ether:ethyl acetate=1:3) to afford tert-butyl N-[(1s,4s)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(30.0 mg, 34% yield) as a yellow solid. LCMS (ESI⁺) m/z: 552.1 (M+H)⁺.

Step g:

Tert-butyl N-[(1s,4s)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(30.0 mg, 54.3 μmol) was separated by Chiral-SFC (Column: DAICELCHIRALPAK AD (250 mm*30 mm, 10 um). Mobile phase: 45% of EtOH (0.1%NH₃.H₂O) in CO₂. Flow rate: 70 mL/min.) to afford tert-butyl N-[(1S,3′R,4S)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(5.00 mg, 17% yield, R_(t)=2.772 min, single peak) as an off-white solidand tert-butyl N-[(1s, 3′S,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(8.00 mg, 27% yield, R_(t)=2.928 min, single peak) as an off-whitesolid. LC-MS (ESI⁺) m/z: 552.1 (M+H)⁺. The absolute configuration of thediastereomers was assigned arbitrarily.

Step h:

Tert-butyl ((1s, 1′R,4S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)carbamate(5.0 mg, 9.06 μmol) was added into HCl/MeOH (5.00 mL, 4 M) and themixture was stirred at 25° C. for 1 h. The mixture was then concentratedto give a residue. The residue was lyophilized to afford (1s, 1′R,4S)-4-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-aminehydrochloride (4.0 mg, HCl salt, 90% yield) as a yellow solid. LCMS(ESI⁺) m/z: 452.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.62 (s, 1H),8.09˜8.15 (m, 2H), 7.56˜7.59 (m, 2H), 7.27˜7.43 (m, 3H), 4.72 (s, 1H),4.17˜4.21 (m, 2H), 3.08˜3.27 (m, 4H), 2.71˜2.90 (m, 1H), 2.33˜2.38 (m,2H), 1.96-2.11 (m, 6H), 1.75˜1.90 (m, 1H), 1.60˜1.69 (m, 1H); SFC: e.e.=100%, R_(t)=4.576 min. Column Chiralcel OD-3 100×4.6 mm I.D., 3 um.Mobile phase: A: CO₂, B: methanol (0.05% DEA). Gradient: from 5% to 40%of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flowrate: 2.8 mL/min Column temperature: 40° C.

Step i:

Tert-butylN-[(1s,3′S,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(8.0 mg, 14.5 μmol) was added into HCl/MeOH (5.00 mL, 4M) and themixture was stirred at 25° C. for 1 h. The mixture was then concentratedto give a residue. The residue was lyophilized to afford(1s,3′S,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (6.50 mg, HCl salt, 92% yield) as a yellow solid. LCMS(ESI⁺) m/z: 452.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.62 (s, 1H),8.09˜8.15 (m, 2H), 7.56˜7.59 (m, 2H), 7.34˜7.43 (m, 3H), 4.72 (s, 1H),4.17˜4.20 (m, 2H), 3.18˜3.30 (m, 4H), 2.71˜2.83 (m, 1H), 2.31˜2.38 (m,2H), 1.96-2.12 (m, 6H), 1.76˜1.80 (m, 1H), 1.62˜1.69 (m, 1H); SFC: e.e.=100%, R_(t)=4.375 min. Column Chiralcel OD-3 100×4.6 mm I.D., 3 um.Mobile phase: A: CO₂, B: methanol (0.05% DEA). Gradient: from 5% to 40%of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flowrate: 2.8 mL/min Column temperature: 40° C.

Examples 190 and 191: Syntheses of (1r, 3′R,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amineand (1r, 3′S,4S)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine

(1r,4r)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(90 mg, 199 μmol, synthesized via Steps a and b of Examples 188-189) wasbrought forward to intermediate tert-butyl N-[(1r,4r)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamatevia Steps a-d, which were performed in a similar fashion as describedabove in Steps c-f for Examples 188-189.

Step e:

Tert-butyl N-[(1r,4r)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(50.0 mg, 90.6 μmol) was separated by Chiral-SFC (Column: DAICELCHIRALPAK AS (250 mm*50 mm, 10 um). Mobile phase: 30% of EtOH (0.1%NH₃.H₂O) in CO₂. Flow rate: 65 mL/min.) to afford tert-butyl N-[(1r,3′R,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(5.00 mg, 10% yield, R_(t)=3.268 min) was obtained as a yellow solid(LCMS (ESI⁺) m/z: 552.1 (M+H)⁺) and tert-butylN-[(1r,3′S,4S)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(13.0 mg, 26% yield, R_(t)=3.400 min) as a yellow solid (LCMS (ESI⁺)m/z: 552.1 (M+H)⁺).)⁺. The absolute configuration of the diastereomerswas assigned arbitrarily.

Step f:

Tert-butyl N-[(1r, 3′R,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(5.0 mg, 9.06 μmol) was added into HCl/MeOH (5 mL, 4M) and the mixturewas stirred at 25° C. for 1 hour. The mixture was then concentrated togive a residue. The residue was lyophilized to afford (1r, 3′R,4R)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (3.7 mg, HCl salt, 84% yield) as a yellow solid. LCMS(ESI⁺) m/z: 452.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.58 (s, 1H),8.09˜8.15 (m, 2H), 7.58˜7.60 (m, 1H), 7.51˜7.54 (m, 1H), 7.35˜7.42 (m,3H), 4.38 (s, 1H), 4.17˜4.20 (m, 2H), 3.05˜3.32 (m, 4H), 2.31˜2.38 (m,2H), 2.09˜2.15 (m, 1H), 1.96˜2.06 (m, 4H), 1.77˜1.86 (m, 4H); SFC: e.e.=99.1%, R_(t)=5.401 min. Column: Chiralpak AS-3 150×4.6 mm I.D., 3 um.Mobile phase: A: CO₂ B: ethanol (0.05% DEA). Gradient: from 5% to 40% ofB in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min. Flowrate: 2.5 mL/min. Column temp.: 35° C.

Step g:

Tert-butyl N-[(1r, 3′S,4S)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]carbamate(13.0 mg, 23.5 μmol) was added into HCl/MeOH (5 mL, 4M) and the mixturewas stirred at 25° C. for 1 h. The mixture was then concentrated to givea residue. The residue was lyophilized to afford (1r, 3′S,4S)-4-[3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (11.0 mg, HCl salt, 96% yield) as a brown solid. LCMS(ESI⁺) m/z: 452.1 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.58 (s, 1H),8.09˜8.15 (m, 2H), 7.57˜7.61 (m, 1H), 7.51˜7.54 (m, 1H), 7.35˜7.42 (m,3H), 4.38 (s, 1H), 4.17˜4.21 (m, 2H), 3.29˜3.33 (m, 4H), 2.31˜2.38 (m,2H), 2.11˜2.18 (m, 1H), 1.96˜2.06 (m, 4H), 1.78˜1.86 (m, 4H); SFC: e.e.=98.7%, R_(t)=5.817 min. Column: Chiralpak AS-3 150×4.6 mm I.D., 3 um.Mobile phase: A: CO₂ B: ethanol (0.05% DEA). Gradient: from 5% to 40% ofB in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min. Flowrate: 2.5 mL/min. Column temp.: 35° C.

Examples 192: Syntheses of(3S)-1′-[5-(quinolin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (200.0 mg, 1.3 mmol, CAS#889447-19-2), (quinolin-5-yl)boronic acid (674.0 mg, 3.9 mmol, CAS#355386-94-6), Cu(OAc)₂ (472.0 mg, 2.6 mmol) and TEA (722 μL, 5.2 mmol)in DCM (6 mL) was stirred at 40° C. for 12 hours under O₂ atmosphere.The reaction mixture was filtered and concentrated. The residue waspurified by silica gel column (elution: petroleum ether:ethylacetate=100:0˜2:1) to give5-{2-chloro-5H-pyrrolo[2,3-b]pyrazin-5-yl}quinoline (265.0 mg, 0.9 mmol,73% yield) as an off-white solid. LC-MS (ESI⁺) m/z: 280.9 (M+H)⁺.

Step b:

To a mixture of 5-{2-chloro-5H-pyrrolo[2,3-b]pyrazin-5-yl}quinoline(160.0 mg, 0.6 mmol) and(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(310.0 mg, 1.1 mmol, Intermediate I, basified by solid Na₂CO₃) was addedNMP (4 drops). The mixture was stirred at 140° C. for 7 hours. Thereaction mixture was purified by prep-HPLC (basic condition) to give(3S)-1′-[5-(quinolin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(32.2 mg, 0.07 mmol) as a white solid. LC-MS (ESI⁺) m/z: 447.1 (M+H)⁺;¹HNMR (400 MHz, CD₃OD) δ 8.93 (s, 1H), 8.21-8.19 (m, 1H), 7.93-7.88 (m,3H), 7.75-7.70 (m, 2H), 7.37-7.36 (m, 1H), 7.21-7.18 (m, 3H), 6.69 (d,J=3.6 Hz, 1H), 4.13 (d, J=12.8 Hz, 2H), 3.95 (s, 1H), 3.28-3.12 (m, 3H),2.79 (d, J=15.6 Hz, 1H), 1.94-1.81 (m, 2H), 1.62-1.45 (m, 2H).

Example 193: Synthesis of(3S)-1′-[5-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

(3S)-1′-[5-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminewas synthesized as described above for Example 192, coupling2-bromo-3-methyl-5H-pyrrolo[2,3-b]pyrazine (CAS #1260812-97-2) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(CAS #287944-16-5) under the same conditions as Step 1 above for 36 h.Characterization of the final product: LC-MS (ESI⁺) m/z: 416.1 (M+H)⁺;¹HNMR (400 MHz, CD₃OD) δ 7.64 (s, 1H), 7.40-7.38 (m, 1H), 7.23-7.19 (m,3H), 6.53 (d, J=4.0 Hz, 1H), 6.41-6.40 (m, 1H), 4.37 (s, 2H), 4.02-4.00(m, 3H), 3.15-3.08 (m, 3H), 2.84-2.78 (m, 3H), 2.62 (s, 3H), 2.04-1.97(m, 2H), 1.67-1.49 (m, 2H).

Example 194: Synthesis of(3S)-1′-[3-methyl-5-(quinolin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

(3S)-1′-[3-methyl-5-(quinolin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminewas synthesized as described above for Example 192, coupling2-bromo-3-methyl-5H-pyrrolo[2,3-b]pyrazine (CAS #1260812-97-2) and(quinolin-5-yl)boronic acid (CAS #355386-94-6) under the same conditionsas Step 1 above for 36 h. Characterization of the final product: LC-MS(ESI⁺) m/z: 461.1 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.37 (d, J=3.6 Hz,1H), 8.86 (d, J=6.0 Hz, 1H), 8.50-8.37 (m, 2H), 8.16-8.14 (m, 3H), 7.58(d, J=7.2 Hz, 1H), 7.43-7.35 (m, 3H), 7.04 (s, 1H), 4.56 (s, 1H),3.79-3.60 (m, 4H), 3.27-3.23 (m, 2H), 2.64 (s, 3H), 2.33-2.19 (m, 2H),2.02-1.81 (m, 2H).

Example 195: Synthesis of(3S)-1′-{1-phenyl-1Hpyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(200.0 mg, 726.0 μmol, Intermediate I),4-chloro-2H-pyrazolo[3,4-d]pyrimidine (112.0 mg, 726.0 μmol) and DIPEA(632.0 μL, 3.6 mmol) were added in DMF (6 mL), the reaction mixture wasstirred at 80° C. for 2 hours. (Boc)₂O (201.0 μL, 871.0 μmol) was addedand the reaction mixture was stirred at 80° C. for 1 hour. The reactionmixture was concentrated under reduced pressure and purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:70) to afford tert-butylN-[(3S)-1′-{2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 66% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 421.1 (M+H)⁺.

Step b:

Tert-butylN-[(3S)-1′-{2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 475.0 μmol), PhB(OH)₂ (115.0 mg, 950.0 μmol), Cu(OAc)₂ (189.0mg, 950.0 μmol), and DMAP (173.0 mg, 1.4 mmol) were added in THE (10mL), and the reaction mixture was evacuated and refilled for 3 timeswith O₂ and stirred at 80° C. for 72 hours under oxygen (balloon). Thereaction mixture was then concentrated under reduced pressure andpurified by flash silica gel chromatography (petroleum ether:EtOAc=100:0to 100:80) to afford tert-butylN-[(3S)-1′-{1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 21% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 497.1 (M+H)⁺;¹HNMR (400 MHz, DMSO-d₆): δ 8.60 (br, 1H), 8.38 (br, 1H), 8.18 (d, J=8Hz, 2H), 7.59-7.54 (m, 2H), 7.37-7.34 (m, 1H), 7.26-7.19 (m, 4H), 4.85(d, J=9.6 Hz, 1H), 4.42 (br, 2H), 3.64 (br, 2H), 3.15 (d, J=16 Hz, 1H),2.81 (d, J=15.6 Hz, 1H), 1.72-1.65 (m, 4H), 1.36 (s, 9H).

Step c:

Tert-butylN-[(3S)-1′-{1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 100.0 μmol) was added to 4M HCl/MeOH (4 mL), and the reactionmixture was stirred at 25° C. for 2 hours. The reaction mixture was thenconcentrated under reduced pressure, diluted with EtOAc (10 mL), andfiltered to afford(3S)-1′-{1-phenyl-1Hpyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (35.0 mg, 81.0% yield) as a white solid. LC-MS (ESI⁺) m/z:397.1 (M+H)⁺; ¹HNMR (400 MHz, DMSO-d₆): δ 8.72 (br, 1H), 8.54 (br, 3H),8.49 (s, 1H), 8.24 (d, J=7.6 Hz, 2H), 7.67-7.62 (m, 3H), 7.48-7.39 (s,4H), 4.75 (s, 2H), 7.48 (s, 1H), 4.52-4.50 (m, 2H), 3.38-3.35 (m, 1H),3.15 (d, J=16 Hz, 1H), 1.95-1.65 (m, 4H).

Example 245: Synthesis of1-{6-[(3S)-3-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one

Step a:

Tert-butylN-[(3S)-6-fluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(500.0 mg, 770 μmol, Intermediate BY) was dissolved in MeCN/AcOH (10mL/10 mL). Then NCS (123.0 mg, 924 μmol) was added and the mixture wasstirred at 70° C. for 2 hours. The mixture was then diluted with EtOAc(100 mL). The mixture was then washed with saturated NaHCO₃ (50 mL), H₂O(30 mL×3) and brine (60 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (petroleum ether:ethyl acetate=100:0 to 100:20) toafford tert-butylN-[(3S)-1′-[5-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(363 mg, 69% yield) as a yellow oil. LC-MS (ESI+) m/z: 683.0 (M+H)⁺.

Step b:

A solution of tert-butylN-[(3S)-1′-[5-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(363.0 mg, 531 μmol),6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one (87.1 mg, 531μmol, Intermediate BW), Xantphos-Pd-G4 (50.9 mg, 53.1 μmol) and Cs₂CO₃(518.0 mg, 1.59 mmol) in toluene (10.0 mL) was stirred at 70° C. for 12hours under N₂. The reaction mixture was diluted with H₂O (40 mL) andextracted with EtOAc (40 mL×3). The combined organic layers were washedwith brine (50.0 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (EtOAc:MeOH=100:0 to 100:5) to afford tert-butylN-[(3S)-1′-[5-chloro-3-(6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(73.0 mg, 19% yield) as a yellow liquid. LC-MS (ESI⁺) m/z: 719.2 (M+H)⁺.

Step c:

Tert-butylN-[(3S)-1′-[5-chloro-3-(6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(73.0 mg, 101 μmol), trimethylboroxine (86.5 μL, 3.5M in THF),Pd(dppf)Cl₂ (7.39 mg, 10.1 μmol) and K₂CO₃ (27.9 mg, 202 μmol) wereplaced into the solvent of dioxane (5.00 mL) and H₂O (1.00 mL). Thereaction mixture was evacuated and refilled 3 times using N₂. Thereaction mixture was stirred at 90° C. for 12 hours. The reactionmixture was concentrated and H₂O (20 mL) was added, then the solutionwas extracted with ethyl acetate (30 mL×3). The combined organic layerswere washed with brine (50 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (EtOAc:MeOH=100:0 to 100:10) to afford thetert-butylN-[(3S)-6-fluoro-1′-[5-methyl-3-(6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(61.0 mg, 87% yield) as a yellow solid. LC-MS (ESI+) m/z: 699.2 (M+H)⁺.

Step d:

Tert-butylN-[(3S)-6-fluoro-1′-[5-methyl-3-(6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(61.0 mg, 87.2 μmol) was added into HCl/MeOH (5 mL, 4 M). The reactionmixture was stirred at 25° C. for 0.5 hour. The reaction mixture wasconcentrated under reduced pressure and purified by prep-HPLC (HCl) toafford1-{6-[(3S)-3-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-onehydrochloride (23.3 mg, 52% yield) as a yellow solid. LC-MS (ESI⁺) m/z:515.2 (M+H)⁺; ¹H NMR (400 MHz, METHANOL-d₄) δ=7.54-7.57 (m, 1H),7.37-7.39 (m, 1H), 7.08-7.18 (m, 2H), 6.13-6.15 (m, 1H), 4.46 (s, 1H),3.88-3.91 (m, 2H), 3.66-3.79 (m, 2H), 3.62 (s, 3H), 3.16-3.26 (m, 4H),2.75-2.78 (m, 2H), 2.65 (s, 3H), 2.05-2.20 (m, 3H), 1.94-1.99 (m, 1H),1.85-1.88 (m, 1H), 1.69-1.73 (m, 1H).

Example 246: Synthesis of1-{6-[(3S)-3-amino-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one

1-{6-[(3S)-3-amino-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-onehydrochloride was synthesized as described for Example 245 starting withtert-butylN-[(3S)-5-fluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(Intermediate Z) in Step a, which was run at 70° C. for 12 hours insteadof 2 hrs. Characterization for the final product1-{6-[(3S)-3-amino-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-onehydrochloride (59.7 mg, 45% yield, yellow solid): LC-MS (ESI⁺) m/z:515.2 (M+H)⁺; ¹HNMR (400 MHz, DMSO-d₆): δ 13.22 (br, 1H), 8.70 (s, 3H),7.47˜7.49 (m, 1H), 7.34˜7.38 (m, 1H), 7.17˜7.27 (m, 2H), 5.81˜5.83 (m,1H), 4.43˜4.45 (m, 1H), 3.71˜3.85 (m, 2H), 3.63˜3.66 (m, 2H), 3.41˜3.52(m, 2H), 3.34 (s, 3H), 2.90˜3.19 (m, 4H), 2.56 (s, 3H), 1.91˜2.08 (m,4H), 1.59˜1.67 (m, 2H).

Example 247: Synthesis of1-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one

1-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-onewas synthesized as described for Example 245 starting with tert-butylN-[(3S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(Intermediate J) in Step a. Characterization for the final product1-{6-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one(35.0 mg, 69% yield, yellow solid: LC-MS (ESI⁺) m/z: 497.2 (M+H)⁺; ¹HNMR(400 MHz, METHANOL-d₄) 7.53-7.55 (m, 1H), 7.31-7.46 (m, 4H), 6.06-6.08(m, 1H), 4.48 (s, 1H), 3.87-3.90 (m, 2H), 3.67-3.80 (m, 2H), 3.58 (s,3H), 3.20-3.27 (m, 4H), 2.73-2.77 (m, 2H), 2.65 (s, 3H), 2.05-2.19 (m,3H), 1.96-2.01 (m, 1H), 1.83-1.86 (m, 1H), 1.70-1.73 (m, 1H).

Example 248: Synthesis of(3S)-1′-[5-(propan-2-ylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

To a reaction mixture of 2-iodopropane (469.0 mg, 2.8 mmol) and TEA (574μL, 4.1 mmol) in DMF (8 mL) was added tert-butylN-[(3S)-1′-[5-(sodiosulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(300.0 mg, 0.7 mmol, Intermediate DE). The reaction mixture was stirredat 25° C. for 1 hour. The reaction mixture was then quenched with water(20 mL), and extracted with EtOAc (50 mL×2). The organic layers werewashed with water (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (40 g column, EtOAc in petroleum ether from 0%-25%) togive tert-butylN-[(3S)-1′-[5-(propan-2-ylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(20.0 mg, 0.04 mmol) as a yellow solid. LC-MS (ESI⁺) m/z: 455.2 (M+H)⁺.

Step b:

The mixture of tert-butylN-[(3S)-1′-[5-(propan-2-ylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(20.0 mg, 0.04 mmol) in HCl/MeOH (2 mL, 4 M) was stirred at 25° C. for0.5 hour. The combined reaction mixture was concentrated to give aresidue. The residue was dissolved in MeOH (5 mL), and the reactionmixture was adjusted to pH=8-9 with solid Na₂CO₃. The mixture wasfiltered, and the filtrate was concentrated to give a residue. Theresidue was purified by prep-HPLC (basic condition) to give(3S)-1′-[5-(propan-2-ylsulfanyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(17.9 mg, 0.05 mmol, combined product) was obtained as a yellow solid.LC-MS (ESI⁺) m/z: 354.9 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J=1.6Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.37-7.35 (m, 1H), 7.23-7.18 (m, 3H),4.22-4.17 (m, 2H), 3.94 (s, 1H), 3.49-3.46 (m, 1H), 3.24-3.12 (m, 3H),2.79 (d, J=15.6 Hz, 1H), 1.87-1.75 (m, 2H), 1.60-1.40 (m, 2H), 1.27 (d,J=6.8 Hz, 6H).

Example 249 and 250: Syntheses of(3S)-1′-[5-(cyclopentylsulfanyl)-3-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amineand(3S)-1′-[5-(cyclopentylsulfanyl)-6-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of sodium5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylpyrazine-2-thiolate(Intermediate DK) and sodium5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methylpyrazine-2-thiolate(Intermediate DL) (250.0 mg, 552.0 μmol), bromocyclopentane (163.0 mg,1.1 mmol) and Cs₂CO₃ (451.0 mg, 1.4 mmol) in DMF (15.0 mL) was stirredat 70° C. for 3 hours under N₂ atmosphere. The mixture was diluted withethyl acetate (40.0 mL), then washed with H₂O (25.0 mL×2). The organicphase was washed with brine (15.0 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (ethyl acetate in petroleumether=0% to 50%) to afford(R)—N—((S)-1′-(5-(cyclopentylthio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-1′-(5-(cyclopentylthio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(230 mg, 84% yield) as a yellow oil. LC-MS (ESI⁺) m/z 499.1 (M+H)⁺.

Step b:

A mixture of(R)—N—((S)-1′-(5-(cyclopentylthio)-3-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-1′-(5-(cyclopentylthio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(220.0 mg, 441.0 μmol) in HCl/MeOH (4M, 10 mL) was stirred at 20° C. for1 hour. The mixture was then concentrated under reduced pressure to givea residue, which was dissolved in MeOH (5.0 mL) and adjusted to pH=8-9with solid Na₂CO₃. The mixture was filtered and concentrated in vacuo togive a residue, which was purified by prep-HPLC (NH₃.H₂O) to afford(3S)-1′-[5-(cyclopentylsulfanyl)-3-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(14.4 mg, 8% yield) as a white solid and(3S)-1′-[5-(cyclopentylsulfanyl)-6-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(39.2 mg, 23% yield) as a white solid. Characterization of(3S)-1′-[5-(cyclopentylsulfanyl)-3-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine:LC-MS (ESI⁺) m/z 395.1 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄): δ 8.00 (s,1H), 7.38 (d, J=4.4 Hz, 1H), 7.25-7.17 (m, 3H), 3.98 (s, 1H), 3.92-3.85(s, 1H), 3.41 (d, J=12.4 Hz, 2H), 3.13-3.01 (m, 3H), 2.76 (d, J=15.6 Hz,1H), 2.51 (s, 3H), 2.15-2.09 (m, 2H), 2.03-1.1.79 (m, 4H), 1.71-1.58 (m,5H), 1.46 (d, J=13.2 Hz, 1H). SFC: e.e.=98.6%, R_(t)=3.007 min,Chiralpak AS-3 100×4.6 mm I.D., 3 um; Mobile phase: A: CO₂, B: ethanol(0.05% DEA); Gradient: from 5% to 40% of B in 4.5 min and hold 40% for2.5 min, then 5% of B for 1 min; Flow rate: 2.8 mL/min; Temperature: 40°C. Characterization of(3S)-1′-[5-(cyclopentylsulfanyl)-6-methylpyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine:LC-MS (ESI⁺) m/z 395.0 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄): δ 7.97 (s,1H), 7.37 (d, J=4.0 Hz, 1H), 7.25-7.16 (m, 3H), 4.16 (d, J=13.2 Hz, 2H),3.94 (s, 1H), 3.88-3.82 (s, 1H), 3.21-3.12 (m, 3H), 2.78 (d, J=15.6 Hz,1H), 2.40 (s, 3H), 2.12-2.02 (m, 2H), 1.91-1.73 (m, 4H), 1.70-1.56 (m,5H), 1.42 (d, J=13.6 Hz, 1H). SFC: e.e.=97.8%, R_(t)=3.377 min, samecolumn conditions as for other regioisomer.

Example 251: Synthesis of(3S)-1′-[5-(cyclopentyloxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of (S′)-tert-butyl(1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(100.0 mg, 217 μmol, Intermediate CZ), Cs₂CO₃ (141.0 mg, 434 μmol),3,4,7,8-tetramethyl-1,10-phenanthroline (10.2 mg, 43.4 μmol) and CuI(4.1 mg, 21.7 μmol) in cyclopentanol (2 mL) was bubbled with N₂ for 5min, then stirred under microwave irradiation at 130° C. for 2 hours.The reaction mixture was filtered and the filtrate was concentrated togive a residue. The residue was purified by prep-HPLC (basic condition)to afford (S)-tert-butyl(1′-(5-(cyclopentyloxy)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(20.0 mg, 20% yield) as a white solid. LC-MS (ESI⁺) m/z. 465.1 (M+H)⁺.

Step b:

The mixture of tert-butylN-[(3S)-1′-[5-(cyclopentyloxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(20.0 mg, 43.0 μmol) in TFA (0.1 mL) and DCM (1.0 mL) was stirred at 25°C. for 0.5 hour. The mixture was then concentrated to give a residue.The residue was dissolved in MeOH (3 mL) and the mixture was adjusted topH=9-10 with solid Na₂CO₃. The mixture was then filtered and thefiltrate was purified by prep-HPLC (basic condition) to afford(3S)-1′-[5-(cyclopentyloxy)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(5.30 mg, 34% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 365.0 (M+H)⁺;¹H NMR (400 MHz, CD₃OD): δ 7.66 (s, 2H), 7.32-7.23 (m, 1H), 7.17-7.00(m, 3H), 5.12 (br t, J=5.3 Hz, 1H), 3.92-3.77 (m, 3H), 3.07-2.93 (m,3H), 2.67 (d, J=15.6 Hz, 1H), 1.90-1.63 (m, 8H), 1.57-1.29 (m, 4H).

Example 252: Synthesis of(1S)-1′-{6-cyclopentylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of 5-bromo-2,3-dihydro-1,3,4-thiadiazol-2-imine (300.0 mg, 1.7mmol, CAS #37566-39-5),(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(781.0 mg, 1.7 mmol, synthesized via Step a of Example 120, 65% purity)and TEA (686.0 μL, 5.0 mmol) in EtOH (25.0 mL) was stirred at 80° C. for4 hours. The mixture was then concentrated in vacuo to give a residue,which was purified by silica gel chromatography (dichloromethane:methanol=0% to 8%) to afford(R)—N-[(3S)-1′-(5-imino-4,5-dihydro-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(1.1 g, 98% yield, 60% purity) as a brown solid. LC-MS (ESI⁺) m/z 406.1(M+H)⁺.

Step b:

A mixture of(R)—N-[(3S)-1′-(5-imino-4,5-dihydro-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(300.0 mg, 443.0 μmol) and 2-chloro-1-cyclopentylethan-1-one (97.3 mg,664.0 μmol, Intermediate DM) in EtOH (10.0 mL) was stirred at 90° C. for12 hours under N₂ atmosphere. The mixture was concentrated under reducedpressure to give a residue, which was purified by silica gelchromatography (dichloromethane: methanol=0% to 13%) to give the crudeproduct as a white solid. The solid was then re-purified by prep-HPLC(HCl) to afford(1S)-1′-{6-cyclopentylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (81.0 mg, 43% yield) as a white solid. LC-MS (ESI⁺) m/z394.0 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄): δ 7.86 (d, J=0.8 Hz, 1H),7.56 (d, J=7.2 Hz, 1H), 7.45-7.35 (m, 3H), 4.49 (s, 1H), 4.02-3.96 (m,1H), 3.89-3.82 (m, 1H), 3.62-3.52 (m, 2H), 3.29-3.25 (m, 1H), 3.24-3.19(m, 2H), 2.24-2.16 (m, 2H), 2.08-1.69 (m, 10H).

Example 253: Synthesis of(1S)-1′-{6-cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of(R)—N-[(3S)-1′-(5-imino-4,5-dihydro-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(200.0 mg, 493.0 μmol, synthesized via Step a of Example 252 and2-bromo-1-cyclopropylethan-1-one (120.0 mg, 739.0 μmol, CAS #69267-75-0)in EtOH (15.0 mL) was stirred at 90° C. for 18 hours under N₂atmosphere. The mixture was then concentrated under reduced pressure togive a residue, which was purified by silica gel chromatography(dichloromethane: methanol=0% to 13%) to give the crude product as awhite solid. The solid was then purified by prep-HPLC (HCl) to afford(1S)-1′-{6-cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (30.1 mg, 15% yield) as a white solid. LC-MS (ESI⁺) m/z366.0 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄): δ 7.77 (s, 1H), 7.55 (d,J=7.2 Hz, 1H), 7.45-7.34 (m, 3H), 4.49 (s, 1H), 4.01-3.94 (m, 1H),3.88-3.82 (m, 1H), 3.62-3.51 (m, 2H), 3.26-3.16 (m, 2H), 2.11-1.91 (m,3H), 1.87-1.81 (m, 1H), 1.74-1.67 (m, 1H), 1.15-1.10 (m, 2H), 0.90-0.86(m, 2H).

Example 254: Synthesis of(1S)-1′-[5-methyl-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of tert-butylN-[(1S)-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(350.0 mg, 555.0 μmol, Intermediate J), pyrrolidine (197.0 mg, 2.8mmol), XantPhos-Pd-G4 (53.3 mg, 55.4 μmol, CAS #1621274-19-8) and Cs₂CO₃(358.0 mg, 1.1 mmol) in toluene (20.0 mL) was stirred at 90° C. for 12hours under N₂ atmosphere. The reaction mixture was concentrated invacuo to give a residue, which was purified by silica gel chromatography(ethyl acetate in petroleum ether=0% to 45%) to afford tert-butylN-[(1S)-1′-[1-(oxan-2-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(180.0 mg, 57% yield) as a yellow solid. LC-MS (ESI⁺) m/z 574.3 (M+H)⁺.

Step b:

To a mixture of tert-butylN-[(1S)-1′-[1-(oxan-2-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(180.0 mg, 313.0 μmol) in MeCN (5.0 mL) and AcOH (5.0 mL) was added NBS(60.8 mg, 344.0 μmol), and the mixture was stirred at 20° C. for 1 hour.The mixture was then concentrated in vacuo to give a residue, which wasdissolved in ethyl acetate (30.0 mL), then washed with sat. NaHCO₃ (20.0mL) and brine (10.0 mL). The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 35%) to afford tert-butylN-[(1S)-1′-[5-bromo-1-(oxan-2-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(130 mg, 64% yield) as a yellow oil. LC-MS (ESI⁺) m/z 654.1 (M+H)⁺.

Step c:

A mixture of tert-butylN-[(1S)-1′-[5-bromo-1-(oxan-2-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(130.0 mg, 199.0 μmol), trimethylboroxine (74.9 mg, 597.0 μmol, CAS#823-96-1), K₂CO₃ (54.9 mg, 398.0 μmol) and Pd(dppf)Cl₂ (14.5 mg, 19.9μmol) in 1,4-dioxane (10.0 mL) and H₂O (3.0 mL) was stirred at 90° C.for 12 hours under N₂ atmosphere. The reaction mixture was thenconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (ethyl acetate in petroleum ether=0% to 40%)to afford tert-butylN-[(1S)-1′-[5-methyl-1-(oxan-2-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(80.0 mg, 69% yield) as a yellow solid. LC-MS (ESI⁺) m/z 588.3 (M+H)⁺.

Step d:

A mixture of tert-butylN-[(1S)-1′-[5-methyl-1-(oxan-2-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(80.0 mg, 136.0 μmol) in HCl/MeOH (2M, 3 mL) was stirred at 20° C. for 2hours. The mixture was then concentrated under reduced pressure to givea residue, which was purified by prep-HPLC (HCl) to afford(1S)-1′-[5-methyl-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (36.5 mg, 61% yield) as a red solid. LC-MS (ESI⁺) m/z404.1 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄): δ 7.56 (d, J=7.6 Hz, 1H),7.45-7.35 (m, 3H), 4.48 (s, 1H), 4.09-3.84 (m, 6H), 3.42-3.33 (m, 2H),3.22 (s, 2H), 2.66 (s, 3H), 2.16-1.68 (m, 8H).

Example 255: Synthesis of(3S)-1′-[5-cyclopropyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of tert-butylN-[(3S)-1′-[5-bromo-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(170.0 mg, 255.0 μmol, synthesized via Steps a-b of Example 152),cyclopropylboronic acid (54.7 mg, 637.0 μmol), K₂CO₃ (105.0 mg, 764.0μmol), SPhos (20.8 mg, 50.9 μmol) and Pd₂(dba)₃ (23.2 mg, 25.4 μmol) intoluene (20.0 mL) was stirred at 100° C. for 12 hours under N₂atmosphere. The mixture was then concentrated in vacuo to give aresidue, which was dissolved in ethyl acetate (30.0 mL) and washed withH₂O (20.0 mL×2). The organic phase was washed with brine (10.0 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by silica gel chromatography (ethylacetate in petroleum ether=0% to 25%) to afford tert-butylN-[(3S)-1′-[5-cyclopropyl-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(110.0 mg, 69% yield) as a yellow oil. LC-MS (ESI⁺) m/z 628.4 (M+H)⁺.

Step b:

A mixture of tert-butylN-[(3S)-1′-[5-cyclopropyl-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(110.0 mg, 175.0 μmol) in HCl/MeOH (2M, 5 mL) was stirred at 20° C. for2 hours. The mixture was concentrated under reduced pressure to give aresidue, which was purified by prep-HPLC (HCl) to afford(3S)-1′-[5-cyclopropyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (73.2 mg, 87% yield) as a yellow solid. LC-MS (ESI⁺) m/z444.1 (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄): δ 7.56 (d, J=7.2 Hz, 1H),7.45-7.35 (m, 3H), 4.49 (s, 1H), 4.26-4.14 (m, 2H), 3.93 (s, 4H),3.46-3.37 (m, 2H), 3.22 (s, 2H), 2.30-2.22 (m, 1H), 2.14-2.07 (m, 1H),2.02-1.96 (m, 1H), 1.88-1.80 (m, 7H), 1.73-1.70 (m, 1H), 1.21-1.15 (m,4H).

Example 256: Synthesis of(S)-(5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)(phenyl)methanone

Step a:

(S)-tert-butyl(1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(100 mg, 217 μmol, Intermediate CZ), (1-phenylethenyl)boronic acid (38.4mg, 260 μmol), Pd(dppf)Cl₂ (15.8 mg, 21.7 μmol) and Cs₂CO₃ (141 mg, 434μmol) were placed into a solution of dioxane (10 mL) and H₂O (1 mL). Thereaction mixture was evacuated and refilled 3 times using N₂. Thereaction mixture was then stirred at 100° C. for 12 hours. The reactionmixture was then concentrated and H₂O (30 mL) was added, and thesolution was extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine (50 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:20) to afford (S)-tert-butyl(1′-(5-(1-phenylvinyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(90.0 mg, 87% yield) as a yellow oil LC-MS (ESI⁺) m/z: 483.1 (M+H)⁺.

Step b:

A mixture of tert-butylN-[(3S)-1′-[5-(1-phenylethenyl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(90.0 mg, 186 μmol), K₂OsO₄.2H₂O (92.7 mg, 279 μmol) and NaIO₄ (59.6 mg,279 μmol) in acetone (10.00 mL) and H₂O (5.00 mL) was stirred at 25° C.for 2 hours. The mixture was then diluted with ethyl ether (30 mL) andH₂O (20 mL). The mixture was filtered and the partitioned layers wereseparated. The aqueous phase was extracted with ethyl acetate (30 mL×3).The combined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (ethylacetate/petroleum ether=0/100 to 40/100) to give tert-butylN-[(3S)-1′-(5-benzoylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(60.0 mg, 67% yield) as a yellow oil LC-MS (ESI⁺) m/z: 507.1 (M+H)⁺.

Step c:

A solution of (S)-tert-butyl(1′-(5-benzoylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(40 mg, 82.5 μmol) in TFA (0.1 mL and DCM (1 mL) was stirred at 25° C.for 1 hour. The mixture was then adjusted to pH=9-10 with solid Na₂CO₃.The mixture was filtered and the filtrate was concentrated to give aresidue. The residue was dissolved in MeCN (3 mL) and was purified byprep. HPLC (basic condition) to give(S)-(5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)(phenyl)methanone(6.50 mg, 16.9 μmol, 21% yield) as a white solid. LC-MS (ESI⁺) m/z 385.1(M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄) δ=8.74 (s, 1H), 8.30 (s, 1H), 7.97(d, J=7.8 Hz, 2H), 7.67-7.60 (m, 1H), 7.56-7.48 (m, 2H), 7.42-7.37 (m,1H), 7.30-7.20 (m, 3H), 4.48 (d, J=13.8 Hz, 2H), 4.01 (s, 1H), 3.48-3.39(m, 2H), 3.21 (d, J=15.8 Hz, 1H), 2.87 (d, J=15.9 Hz, 1H), 1.97-1.76 (m,2H), 1.72-1.61 (m, 1H), 1.51 (d, J=13.9 Hz, 1H).

Example 257: Synthesis of(3S)-1′-{5-[(hydroximino)(phenyl)methyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of tert-butylN-[(3S)-1′-(5-benzoylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50 mg, 0.1 mmol, synthesized via Steps a and b of Example 256),NH₂OH.HCl (70.8 mg, 1.0 mmol), TEA (713 ul, 5.2 mmol) and NH₂OH.HCl (286mg, 4.1 mmol) in MeOH (5.0 mL) and was stirred at 25° C. for 2 h. Themixture was diluted with ethyl ether (30 mL) and H₂O (20 mL). Themixture was then filtered and the partitioned layers were separated. Theaqueous phase was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (ethyl acetate/petroleumether=0/100 to 80/100) to give (S,E)-tert-butyl(1′-(5-((hydroxyimino)(phenyl)methyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(80 mg, 53% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 500.2 (M+H)⁺.

Step b:

A solution of tert-butylN-[(3S)-1′-{5-[(E)-(hydroxyimino)(phenyl)methyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(80 mg, 160 μmol) in HCl/MeOH (10 ml) was stirred at 25° C. for 1 hour.The mixture was then adjusted to pH=9-10 with solid Na₂CO₃. The mixturewas filtered and the filtrate was concentrated to give a residue. Theresidue was dissolved in HCl/MeOH (10 mL). The mixture was purified byprep. HPLC (basic condition) to give(3S)-1′-{5-[(hydroxyimino)(phenyl)methyl]pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine;formic acid (9.30 mg, 13% yield) as a white solid. LC-MS (ESI⁺) m/z:385.1. (M+H)⁺; ¹HNMR (400 MHz, Methanol-d₄) δ=8.61-8.43 (m, 2H),8.35-8.26 (m, 1H), 7.57-7.27 (m, 10H), 7.61-7.24 (m, 1H), 4.46-4.26 (m,3H), 3.44-3.35 (m, 2H), 3.26-3.11 (m, 2H), 1.95-1.78 (m, 2H), 1.76-1.59(m, 2H), 10.35-1.23 (m, 1H).

Example 258: Synthesis of{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyridin-2-yl}methanol

Step a:

A mixture of methyl 6-bromo-3-fluoropyridine-2-carboxylate (500.0 mg,2.1 mmol, CAS #1214332-47-4),(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(586.0 mg, 2.1 mmol, Intermediate I) and TEA (1.46 mL, 10.6 mmol) in DMF(50.0 mL) was stirred at 80° C. for 3 hours. The reaction mixture wasused directly without further workup. LC-MS (ESI⁺) m/z 417.9 (M+H)⁺.

Step b:

To the mixture of methyl3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-bromopyridine-2-carboxylate(886.0 mg, 2.1 mmol) in DMF (50.0 mL) was added (Boc)₂O (722 μL, 3.2mmol), the mixture was stirred at 20° C. for 2 hours. The mixture wasthen diluted with ethyl acetate (120.0 mL), and washed with H₂O (80.0mL×2). The organic phase was washed with brine (50.0 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue,which was purified by silica gel chromatography (ethyl acetate inpetroleum ether=0% to 35%) to afford methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyridine-2-carboxylate(700 mg, 64% yield) as a yellow solid. LC-MS (ESI⁺) m/z 538.0 (M+Na)⁺.

Step c:

A mixture of methyl6-bromo-3-[(3S)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyridine-2-carboxylate(320.0 mg, 619.0 μmol), 3-chloro-4-(sodiosulfanyl)pyridin-2-amine (146.0mg, 804.0 μmol, Intermediate AC), XantPhos (71.1 mg, 123.0 μmol), DIPEA(352.0 μL, 1.9 mmol) and Pd₂(dba)₃ (56.6 mg, 61.9 μmol) in 1,4-dioxane(15.0 mL) was stirred at 100° C. for 12 hours under N₂ atmosphere. Themixture was then concentrated in vacuo to give a residue, which waspurified by silica gel chromatography (ethyl acetate in petroleumether=0% to 85%) to afford (S)-methyl6-((2-amino-3-chloropyridin-4-yl)thio)-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)picolinate(290.0 mg, 79% yield) as a brown solid. LC-MS (ESI⁺) m/z 596.1 (M+H)⁺.

Step d:

To a mixture of (S)-methyl6-((2-amino-3-chloropyridin-4-yl)thio)-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)picolinate(290.0 mg, 486.0 μmol) in anhydrous THE (10.0 mL) was added DIBAL-H(2.42 mL, 2.42 mmol) slowly at 0° C., then the resulting mixture waswarmed to 15° C. and stirred for 5 hours under N₂ atmosphere. Themixture was quenched with 10% AcOH (20.0 mL), then extracted with ethylacetate (20.0 mL×2). The organic phases were washed with sat. NaHCO₃(20.0 mL) and brine (10.0 mL). The organic phases were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue,which was purified by silica gel chromatography (methanol indichloromethane=0% to 8%) to afford tert-butylN-[(3S)-1′-{6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-2-(hydroxymethyl)pyridin-3-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 18% yield) as a yellow solid. LC-MS (ESI⁺) m/z 568.1 (M+H)⁺.

Step e:

A mixture of tert-butylN-[(3S)-1′-{6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-2-(hydroxymethyl)pyridin-3-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 88.0 μmol) in HCl/EtOAc (4M, 2.0 mL) and EtOAc (2.0 mL) wasstirred at 15° C. for 1 hour. The mixture was concentrated under reducedpressure to give a residue, which was dissolved in MeOH (5.0 mL) andadjusted to pH=8.0 with solid Na₂CO₃. The mixture was filtered andconcentrated in vacuo to give a residue, which was purified by prep-HPLC(NH₃.H₂O) to afford{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyridin-2-yl}methanol(4.2 mg, 10% yield) as a white solid. LC-MS (ESI⁺) m/z 490.0 (M+Na)⁺;¹HNMR (400 MHz, Methanol-d₄): δ 7.66-7.64 (m, 2H), 7.55 (d, J=8.0 Hz,1H), 7.43-7.40 (m, 1H), 7.27-7.22 (m, 3H), 6.17 (d, J=5.6 Hz, 1H), 4.78(s, 2H), 4.05 (s, 1H), 3.21-3.12 (m, 3H), 3.06-2.99 (m, 2H), 2.82 (d,J=16.0 Hz, 1H), 2.08-1.96 (m, 2H), 1.69-1.64 (m, 1H), 1.55-1.51 (m, 1H).

Examples 259 & 260: Syntheses of(1R)-1-{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}ethan-1-oland(1S)-1-{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}ethan-1-ol

Step a:

To a solution of methyl3-[(3S′)-3-{[(tert-butoxy)carbonyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazine-2-carboxylate(500.0 mg, 810 μmol, synthesized via Step a of Example 243) in THF(15.00 mL) was added DIBAL-H (806 μL, 1.21 mmol, 1.5 M in toluene) at−78° C. under N₂. The solution was stirred for 2 hours at the sametemperature. The reaction was quenched by a solution of 10% aqueous AcOH(50 mL) at −78° C. and extracted with EtOAc (50 mL×3). The combinedorganic layer was adjusted pH to 8˜9 with saturated aqueous of NaHCO₃and separated. The organic layer was washed with brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (petroleumether:ethyl acetate=100:0 to 100:30). The product tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]-3-formylpyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(260.0 mg, 55% yield) was obtained as a yellow solid. LC-MS (ESI⁺) m/z:586.0 (M+H)⁺. The side product tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]-3-(hydroxymethyl)pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120 mg, 25% yield) was also obtained as a yellow oil. LC-MS (ESI⁺) m/z:588.0 (M+H)⁺.

Step b:

To a mixture of tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]-3-formylpyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 340 μmol) in THE (3.00 mL) was added MeMgBr (153 μL, 462μmol, 3M in diethyl ether) slowly at −78° C. The mixture was warmed to0° C. for 1 hour. Another MeMgBr (153 μL, 462 μmol, 3M in diethyl ether)was added at 0° C. The mixture was stirred at 0° C. for 1 hour. Thereaction was then quenched with H₂O (10 mL). The mixture was filteredand the filtrate was extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by column chromatography (petroleum ether/ethyl acetate=100:0to 100:30) to afford tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]-3-(1-hydroxyethyl)pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(202 mg, 335 μmol, 99% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 602.1(M+H)⁺.

Step c:

Tert-butylN-[(3S)-1′-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]-3-(1-hydroxyethyl)pyrazin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 331 μmol) was dissolved in EtOAc (2.00 mL). Then HCl/EtOAc(2.00 mL, 4 M) was added and the mixture was stirred at 25° C. for 1hour. The yellow solid that precipitated was collected by filtration.The solid was dissolved in MeOH (5.00 mL). The mixture was adjusted topH=8-9 with solid NaHCO₃. The mixture was filtered and the filtrate waspurified by prep-HPLC (HCOOH) to afford1-{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}ethan-1-ol;formic acid (100.0 mg, HCOOH salt, 55% yield) as a yellow solid. LC-MS(ESI⁺) m/z: 502.0 (M+H)⁺.

Step d:

1-{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}ethan-1-ol(100.0 mg, 199 μmol, HCOOH salt) was basified with solid NaHCO₃ andseparated by Chiral-SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um;mobile phase: 50% of EtOH (0.1% NH₃.H₂O) in CO₂; flow rate: 70 mL/min)to give two diastereomers, which were further purified by a second prep.HPLC (HCOOH condition). The absolute configuration of the diastereomerswere arbitrarily assigned.(1R)-1-{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}ethan-1-ol;formic acid (26.2 mg, 24% yield) was obtained as a white solid: LC-MS(ESI⁺) m/z: 502.0 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.53 (s, 1H), 8.39(s, 1H), 8.05 (d, J=5.4 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 7.45-7.30 (m,3H), 6.90 (d, J=5.4 Hz, 1H), 5.10 (q, J=6.4 Hz, 1H), 4.42 (s, 1H),4.01-3.88 (m, 1H), 3.86-3.77 (m, 1H), 3.42-3.36 (m, 1H), 3.32-3.26 (m,1H), 3.23-3.10 (m, 2H), 2.09-1.90 (m, 2H), 1.79 (m, 1H), 1.67 (m, 1H),1.54 (d, J=6.4 Hz, 3H); SFC: e.e. =100%, R_(t)=1.561 min. Column:Chiralpak AD-3 50×4.6 mm I.D., 3 m. Mobile phase: 40% of ethanol (0.05%DEA) in CO₂. Flow rate: 4 mL/min. Column temperature: 35° C.(1S)-1-{3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}ethan-1-ol;formic acid (19.8 mg, 18% yield) was obtained as a white solid: LC-MS(ESI⁺) m/z: 502.0 (M+H)⁺; ¹HNMR (400 MHz, CD₃OD): δ 8.55 (s, 1H), 8.39(s, 1H), 8.05 (d, J=5.4 Hz, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.42-7.29 (m,3H), 6.90 (d, J=5.4 Hz, 1H), 5.09 (q, J=6.3 Hz, 1H), 4.36 (s, 1H),4.09-3.97 (m, 1H), 3.80-3.69 (m, 1H), 3.45-3.34 (m, 1H), 3.31-3.22 (m,1H), 3.21-3.09 (m, 2H), 2.08 (m, 1H), 1.97-1.86 (m, 1H), 1.78-1.64 (m,2H), 1.53 (d, J=6.4 Hz, 3H. SFC: e.e. =100%, R_(t)=2.320 min with sameconditions as stated for other diastereomer.

Example 261: Synthesis of2-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-[(2,3-dichlorophenyl)sulfanyl]-3,4-dihydropyrimidin-4-one

Step a:

A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (1.00 g, 4.5 mmol, CAS#57054-92-9), (3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminedihydrochloride (1.40 g, 4.9 mmol, Intermediate I) and TEA (3.10 mL,22.3 mmol) in DMF (20.00 mL) was stirred at 50° C. for 1 hour. Themixture was used in next step directly. LC-MS (ESI⁺) m/z: 388.9, 390.9(M+H)⁺.

Step b:

To a mixture of(3S)-1′-(5-bromo-4-methoxypyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine(1.70 g, 4.5 mmol) in DMF (20.00 mL) was added (Boc)₂O (1.50 mL, 6.7mmol). The mixture was stirred at 25° C. for 3 hours. The mixture wasthen diluted with EtOAc (100 mL), washed with H₂O (30 mL×3), brine (50mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by flash silica gel chromatography(petroleum ether:ethyl acetate=100:0 to 100:20) to afford tert-butylN-[(3S)-1′-(5-bromo-4-methoxypyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(2.20 g, 100% yield) as a white solid. LC-MS (ESI⁺) m/z: 489.0, 491.0(M+H)⁺.

Step c:

Tert-butylN-[(3S)-1′-(5-bromo-4-methoxypyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(300.0 mg, 612 μmol) and 2,3-dichlorobenzene-1-thiol (120.0 mg, 673μmol) were dissolved in dioxane (20.0 mL). Then XantPhos (70.5 mg, 122μmol), Pd₂(dba)₃ (55.9 mg, 61.2 μmol) and DIPEA (318 μL, 1.8 mmol) wereadded in turn. The mixture was evacuated and refilled 3 times using N₂.The reaction mixture was then stirred at 120° C. for 10 hours. Thesolvent was then removed under reduced pressure to give a black residue,which was purified by column chromatography (petroleum ether/EtOAc=100:0to 100:60) to afford tert-butylN-[(3S)-1′-{5-[(2,3-dichlorophenyl)sulfanyl]-4-methoxypyrimidin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(260.0 mg, 72% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 609.1(M+Na)⁺.

Step d:

Tert-butylN-[(3S)-1′-{5-[(2,3-dichlorophenyl)sulfanyl]-4-methoxypyrimidin-2-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(50.0 mg, 85.0 μmol) was placed into aq. HBr (48%, 20 mL). The reactionmixture was stirred at 100° C. for 6 hours. The mixture was thenconcentrated to give a residue. The residue was dissolved in MeOH (2.00mL) and adjusted to pH=7-8 with solid Na₂CO₃, then purified by prep-HPLC(FA) to afford2-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-[(2,3-dichlorophenyl)sulfanyl]-3,4-dihydropyrimidin-4-one(6.80 mg, 17% yield) as a white solid. LC-MS (ESI⁺) m/z: 472.9 (M+H)⁺;¹H NMR (400 MHz, Methanol-d₄) δ 8.02 (s, 1H), 7.42 (d, J=7.4 Hz, 1H),7.34-7.17 (m, 4H), 7.05 (t, J=8.0 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H),4.43-4.28 (m, 2H), 4.16 (d, J=13.9 Hz, 1H), 3.45-3.28 (m, 2H), 3.17-3.03(m, 2H), 2.12-1.46 (m, 4H).

Example 262: Synthesis of(S)-1′-(5-((2,3-dichlorophenyl)thio)-4-methoxypyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

(S)-tert-butyl(1′-(5-((2,3-dichlorophenyl)thio)-4-methoxypyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(50.0 mg, 85.0 μmol, synthesized via Steps a-c of Example 261) wasplaced into HCl/EtOAc (10 mL, 4 M). The mixture was then stirred at 25°C. for 2 h. The mixture was then concentrated and was purified byprep-HPLC (FA) to afford(S)-1′-(5-((2,3-dichlorophenyl)thio)-4-methoxypyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineformate (19.4 mg, HCOOH salt 43% yield) as a white solid. LC-MS (ESI⁺)m/z: 487.0 (M+H)⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 8.55 (s, 1H), 8.22(s, 1H), 7.49 (d, J=7.3 Hz, 1H), 7.41-7.26 (m, 4H), 7.12 (t, J=8.0 Hz,1H), 6.63 (d, J=8.1 Hz, 1H), 4.78-4.65 (m, 2H), 4.31 (s, 1H), 3.97-3.89(m, 3H), 3.47-3.36 (m, 2H), 3.27-3.18 (m, 1H), 3.16-3.05 (m, 1H), 1.81(d, J=4.2, 12.4 Hz, 2H), 1.72-1.57 (m, 2H).

Example 263: Synthesis of(S)-1′-(5-(((6-chloropyridin-2-yl)methyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

To a solution of ethyl(S)-3-((5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(190 mg, 371 umol, Intermediate ED) and 2-(bromomethyl)-6-chloropyridine(191 mg, 927 umol, CAS #63763-79-1) in THF (8.00 mL) was added asolution of EtONa (101 mg, 1.48 mmol) in EtOH (1.60 mL) at 0° C. Thenthe mixture was stirred at 0 to 25° C. for 16 h. The mixture was thenpoured into water (50.0 mL) and extracted with ethyl acetate (50.0mL×2). The combined organic layers were washed with brine (50.0 mL×2),dried over Na₂SO₄, filtered and concentrated to give tert-butyl(S)-(1′-(5-(((6-chloropyridin-2-yl)methyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(335 mg, quant. crude yield) as light yellow oil. LC-MS (ESI⁺) m/z:538.3 (M+H)⁺.

Step b:

To a solution of tert-butyl(S)-(1′-(5-(((6-chloropyridin-2-yl)methyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(320 mg, 595 umol) in DCM (12.8 mL) was added TFA (1.97 g, 17.3 mmol,1.28 mL) at 25° C. The mixture was stirred at 25° C. for 12 h. Themixture was then adjusted the pH to 7˜8 with saturated NaHCO₃ solutionand extracted with DCM (20.0 mL×3). The organic layer was washed withbrine (20.0 mL×2), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP150*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 16%-46%, 10min) to give(S)-1′-(5-(((6-chloropyridin-2-yl)methyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(79.2 mg, 158 umol, 27% yield) as a light yellow solid. LC-MS (ESI⁺)m/z: 438.2 (M+H)⁺; ¹H NMR (400 MHz DMSO-d₆): δ 8.30-8.26 (m, 2H), 8.03(d, J=1.2 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H), 7.38-7.32 (m, 3H), 7.22-7.17(m, 3H), 4.31 (s, 2H), 4.16-4.12 (m, 2H), 3.91 (s, 1H), 3.16-3.05 (m,3H), 2.70-2.66 (m, 1H), 1.78-1.62 (m, 2H), 1.49 (br d, J=12.8 Hz, 1H),1.16 (br d, J=12.8 Hz, 1H).

Example 264: Synthesis of(S)-1′-(5-((cyclopentylmethyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

(S)-1′-(5-((cyclopentylmethyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminewas synthesized as described above for Example 263, coupling ethyl(S)-3-((5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)propanoate(Intermediate ED) and (bromomethyl)cyclopentane in Step a.Characterization of(S)-1′-(5-((cyclopentylmethyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LC-MS (ESI⁺) m/z: 395.2 (M+H)⁺; ¹H NMR (400 MHz DMSO-d₆): δ 8.34-8.27(m, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.33-7.31 (m, 1H), 7.21-7.14 (m, 3H),4.14-4.09 (m, 2H), 3.88 (s, 1H), 3.18-2.99 (m, 5H), 2.65 (br d, J=16.0Hz, 1H), 2.09-1.98 (m, 1H), 1.80-1.44 (m, 10H), 1.27-1.19 (m, 2H), 1.13(br d, J=12.4 Hz, 1H).

Example 265: Synthesis of(S)-1′-(5-(phenethylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

To a solution of (2-bromoethyl)benzene (696 mg, 3.76 mmol, 508 uL) andTEA (571 mg, 5.64 mmol, 785 uL) in DMF (15.0 mL) was added sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate(350 mg, 805 umol, Intermediate DE) at 25° C., and the mixture wasstirred at 25° C. for 1 h. The reaction mixture was poured into water(50.0 mL) and extracted with ethyl acetate (50.0 mL×3). The organiclayer was washed with brine (50.0 mL×2), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-HPLC (column: PhenomenexSynergi C18 150*25 * 10 um; mobile phase: [water (0.225% FA)-ACN]; B %:70%-100%, 10 min) to give tert-butyl(S)-(1′-(5-(phenethylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(130 mg, 30% yield) as a light yellow solid. LC-MS (ESI⁺) m/z: 517.3(M+H)⁺.

Step b:

To a solution of tert-butyl(S)-(1′-(5-(phenethylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(150 mg, 290 umol) in MeOH (5.00 mL) was added HCl/MeOH (4 M, 2.00 mL)at 25° C., and the mixture was stirred at 25° C. for 12 h. The mixturewas then concentrated under vacuum. The residue was dissolved with MeOH(4.00 mL) and pH of the mixture was adjusted to 8˜9 with ammoniumhydroxide (25˜28%). The mixture was purified by prep-HPLC (column:Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammoniahydroxide v/w)-ACN]; B %: 56%-86%, 10 min) to give a residue. Theresidue was dissolved with CH₃CN (3.00 mL) and to the mixture was addeda solution of HCOOH (78.7 mg, 1.64 mmol) in H₂O (30.0 mL). The mixturewas lyophilized to give(S)-1′-(5-(phenethylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(57.3 mg, 120 umol, 85% yield) as a light yellow solid. LC-MS (ESI⁺)m/z: 417.2 (M+H)⁺; ¹H NMR (400 MHz DMSO-d₆): δ 8.31 (d, J=1.2 Hz, 1H),8.25 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.35-7.18 (m, 9H), 4.14 (br d,J=13.2 Hz, 2H), 3.94 (s, 1H), 3.27-3.24 (m, 2H), 3.17-3.06 (m, 4H), 2.87(t, J=7.6 Hz, 2H), 2.69 (d, J=16.0 Hz, 1H), 1.08-1.73 (m, 1H), 1.71-1.63(m, 1H), 1.50 (br d, J=12.8 Hz, 1H), 1.18 (br d, J=14.4 Hz, 1H).

Example 266: Synthesis of(S)-1′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

(S)-1′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminewas synthesized as described for Example 265, coupling sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate(Intermediate DE) with (bromomethyl)cyclopropane with TEA as a base inStep a. Characterization of(S)-1′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine:LC-MS (ESI⁺) m/z: 350.2 (M−17)⁺; ¹H NMR (400 MHz DMSO-d₆): δ 8.28-8.25(m, 2H), 8.07 (d, J=1.6 Hz, 1H), 7.34-7.33 (m, 1H), 7.22-7.17 (m, 3H),4.15-4.10 (m, 2H), 3.92 (s, 1H), 3.16-3.05 (m, 4H), 2.95 (d, J=6.8 Hz,2H), 2.69 (br d, J=10.0 Hz, 1H), 1.80-1.62 (m, 2H), 1.49 (br d, J=3.2Hz, 1H), 1.17 (br d, J=14.0 Hz, 1H), 1.04-0.97 (m, 1H), 0.51-0.47 (m,2H), 0.22-0.19 (m, 2H).

Example 267: Synthesis of(S)-2-((5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)-1-(p-tolyl)ethan-1-one

(S)-2-((5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)-1-(p-tolyl)ethan-1-onewas synthesized as described for Example 265, coupling sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate(Intermediate DE) with 2-bromo-1-(p-tolyl)ethan-1-one (CAS #619-41-0)using TEA as the base in Step a, which was run at rt for 12 h. In Stepb, TFA in DCM was used in place of HCl in MeOH for the deprotection.Characteration of(S)-2-((5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)thio)-1-(p-tolyl)ethan-1-one:LC-MS (ESI⁺) m/z: 445.2 (M+H)⁺; ¹H NMR (400 MHz DMSO-d₆): δ 8.25-8.22(m, 2H), 8.06 (d, J=1.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.34 (br d,J=7.6 Hz, 3H), 7.20-7.18 (m, 3H), 4.57 (s, 2H), 4.13 (br d, J=13.6 Hz,2H), 3.94 (s, 1H), 3.15-3.05 (m, 4H), 2.69 (br d, J=15.6 Hz, 1H), 2.39(s, 3H), 1.78-1.62 (m, 2H), 1.48 (br d, J=13.6 Hz, 1H), 1.17 (br d,J=13.6 Hz, 1H).

Example 268: Synthesis of(R)-(3-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol

Step a:

To a solution of ethyl3-chloro-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate (382 mg,1.10 mmol, Intermediate EI) and DIPEA (428 mg, 3.31 mmol, 577 uL) in DMF(5.00 mL) was added (R)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (337mg, 1.21 mmol, Intermediate CB, 2HCl) at 20° C. The solution was heatedto 100° C. and stirred for 15 h. The reaction mixture was diluted withH₂O (20.0 mL), then filtered and the filter cake was dried under reducedpressure to give ethyl(R)-3-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate(498 mg, 88% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 513.4 (M+H)⁺;¹H NMR (400 MHz MeOD): δ 7.64-7.62 (m, 1H), 7.43-7.39 (m, 2H), 7.37-7.35(m, 1H), 7.20 (t, J=6.4 Hz, 1H), 6.94-6.70 (m, 1H), 6.82 (d, J=8.0 Hz,1H), 4.12-4.36 (m, 2H), 4.18 (s, 1H), 4.10-4.93 (m, 2H), 3.55-3.47 (m,2H), 2.27 (s, 3H), 1.98-1.97 (m, 1H), 1.83-1.82 (m, 3H), 1.39-1.28 (m, 3H).

Step b:

To a solution of ethyl(R)-3-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate(498 mg, 970 umol) in DCM (10.0 mL) was added DIBAL-H (1 M, 3.88 mL) at−78° C. under N₂. The solution was stirred at −78° C. for 2 h. Thereaction mixture was quenched by addition brine (30.0 mL) at −20° C.,and then filtered and the filtrate was extracted with DCM (20.0 mL×3).The combined organic layers were washed with brine (10.0 mL×2), driedover Na₂SO₄ and concentrated under reduced pressure to give a residue,which was purified by pre-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B %: 30%-60%, 9 min) to give(R)-(3-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol(30.0 mg, 57.2 umol, 5% yield) as an off-white solid. LC-MS (ESI⁺) m/z:471.3 (M+H)⁺; ¹H NMR (400 MHz MeOD): δ 8.51 (s, 1H), 7.65-7.63 (m, 1H),7.47-7.45 (d, J=7.6 Hz, 1H), 7.42-7.41 (d, J=7.6 Hz, 1H), 7.37-7.35 (m,1H), 7.29 (t, J=5.6 Hz, 1H), 6.97 (t, J=14.4 Hz, 1H), 6.89 (d, J=8.0 Hz,1H), 4.71 (s, 2H), 4.39 (s, 1H), 3.90 (d, J=13.2 Hz, 1H), 3.75 (d,J=13.6 Hz, 1H), 3.47-3.41 (m, 2H), 2.28 (s, 3H), 2.21 (s, 1H), 2.05-2.01(m, 2H), 1.89-1.86 (m, 1H).

Example 269: Synthesis of(S)-(3-(1-amino-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol

(S)-(3-(1-amino-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanolwas synthesized as described above in Example 268, coupling ethyl3-chloro-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate(Intermediate EI) with(S)-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(Intermediate T) in Step a; and allowing Step b to come to rt stirringfor 12 hr.(S)-(3-(1-amino-4-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanolwas purified by pre-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.1% TFA)-ACN]; B %: 30%-60%, 13 min) to give thecompound (39.8 mg, 65.5 umol, 7% yield, TFA): LC-MS (ESI⁺) m/z: 487.1(M+H)⁺; ¹H NMR (400 MHz MeOD): δ 7.64 (dd, J=1.6 Hz, 8.0 Hz, 1H), 7.43(d, J=7.6 Hz, 1H), 7.41-7.38 (m, 1H), 7.36 (dd, J=1.6 Hz, 7.6 Hz, 2H),7.16 (t, J=16.4 Hz, 1H), 4.67 (s, 2H), 4.51 (s, 1H), 3.85-3.81 (m, 1H),3.75-3.72 (m, 1H), 3.26 (d, J=3.2 Hz, 1H), 3.24-3.22 (m, 1H), 3.16 (s,1H), 3.13-3.12 (m, 1H), 2.27 (s, 3H), 2.08-1.91 (m, 2H), 1.81-1.78 (m,1H), 1.70-1.67 (m, 1H).

Example 270: Synthesis of(S)-1′-(6-methyl-4-(thiazol-2-yl)pyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

To a solution of tert-butyl(S)-(1′-(4-iodo-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(860 mg, 1.66 mmol, Intermediate EL), CsF (755 mg, 4.97 mmol, 183 uL)and Pd(PPh₃)₂Cl₂ (116 mg, 166 umol) in dioxane (20.0 mL) was added2-(tributylstannyl)thiazole (929 mg, 2.48 mmol, CAS #121359-48-6) underN₂, then the mixture was stirred at 100° C. for 3 h. The reactionmixture was poured into water (50.0 mL), then the aqueous phase wasextracted with ethyl acetate (50.0 mL×2). The combined organic phase waswashed with brine (50.0 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by silica gelchromatography (100-200 mesh silica gel, petroleum ether/ethylacetate=100/1 to 8/1, Product R_(f)=0.20) to afford tert-butyl(S)-(1′-(6-methyl-4-(thiazol-2-yl)pyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(580 mg, 1.16 mmol, 70% yield) as a yellow solid. LC-MS (ESI⁺) m/z:477.3 (M+H)⁺.

Step b:

To a solution of tert-butyl(S)-(1′-(6-methyl-4-(thiazol-2-yl)pyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(580 mg, 1.22 mmol) in EtOAc (10.0 mL) was added HCl/EtOAc (4 M, 304uL), then the mixture was stirred at 25° C. for 1 h. The reactionmixture was concentrated in vacuo to give a crude product, which wasdiluted with water (20.0 mL). The aqueous phase was extracted ethylacetate (20.0 mL), then the aqueous phase was lyophilized to afford(S)-1′-(6-methyl-4-(thiazol-2-yl)pyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(101.63 mg, 232 umol, 19% yield, HCl) as a yellow solid. LC-MS (ESI⁺)m/z: 377.2 (M+H)⁺; ¹H NMR (400 MHz DMSO): δ 8.74 (s, 2H), 8.13-8.15 (m,2H), 7.64 (d, J=7.6 Hz, 1H), 7.51 (s, 1H), 7.28-7.36 (m, 4H), 4.31-4.46(m, 3H), 3.43-3.49 (m, 2H), 3.25-3.29 (m, 1H), 2.99 (d, J=16.4 Hz, 1H),2.63 (s, 3H), 1.89-1.99 (m, 2H), 1.59-1.70 (m, 2H).

Example 271: Synthesis of(S)-1′-(3-methyl-5-(methylsulfonyl)phenyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of tert-butyl(S)-(1′-(3-bromo-5-methylphenyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(130 mg, 276 umol, Intermediate EM), MeSO₂Na (28.2 mg, 276 umol),L-Proline (6.35 mg, 55.2 umol), K₂CO₃ (7.62 mg, 55.2 umol) and CuI (5.25mg, 27.6 umol) in DMSO (4 mL) was irradiated at 140° C. for 2 h undermicrowave. The reaction mixture was then poured into H₂O (40.0 mL), andthe aqueous phase was extracted with ethyl acetate (40.0 mL×2). Thecombined organic phase was washed with brine (40 mL×2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo to give tert-butyl(S)-(1′-(3-methyl-5-(methylsulfonyl)phenyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(60 mg, 46% yield) as brown oil. LC-MS (ESI⁺) m/z: 471.2 (M+H)⁺.

Step b:

To a solution of tert-butyl(S)-(1′-(3-methyl-5-(methylsulfonyl)phenyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(60 mg, 127 umol) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 319 uL) at25° C. for 1 h. The reaction mixture was concentrated in vacuo to giveresidue, and then the residue was diluted with water (20.0 mL). Theaqueous phase was extracted with ethyl acetate (20.0 mL×2), then theaqueous phase was concentrated in vacuo. The crude product was purifiedby pre HPLC (column: Phenomenex Synergi C₁₈ 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 6%-36%, 10 min), and the eluent wasconcentrated in vacuo to remove ACN. The residual aqueous solution waslyophilized to afford(S)-1′-(3-methyl-5-(methylsulfonyl)phenyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(7.40 mg, 17.4 umol, 14% yield, FA) as a yellow solid. LC-MS (ESI⁺) m/z:317.2 (M+H)⁺; ¹H NMR (400 MHz MeOD-d₄): δ 7.48-7.50 (m, 1H), 7.29-7.37(m, 4H), 7.19 (s, 1H), 7.14 (s, 1H), 4.35-4.37 (m, 1H), 3.65-3.77 (m,2H), 3.05-3.16 (m, 7H), 2.40 (s, 3H), 1.84-1.98 (m, 2H), 1.62-1.74 (m,2H).

Example 272: Synthesis of(S)-1′-(6-((cyclopropylmethyl)thio)pyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineformate

Step a:

To a solution of sodium(S)-5-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridine-2-thiolate(423 mg, 977 umol, Intermediate ER) in DMF (10.0 mL) was added TEA (692mg, 6.84 mmol, 952 uL) and (bromomethyl)cyclopropane (613 mg, 4.54 mmol,435 uL) at 25° C. and the mixture was stirred at 25° C. for 2 h. Thereaction mixture was then poured into water (50.0 mL) and extracted withethyl acetate (50.0 mL×3). The organic layer was washed with brine (50.0mL×2), dried over Na₂SO₄, filtered and concentrated to give tert-butyl(S)-(1′-(6-((cyclopropylmethyl)thio)pyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(500 mg, quant. crude yield) as a yellow solid. LC-MS (ESI⁺) m/z: 466.3(M+H)⁺.

Step b:

To a solution of tert-butyl(S)-(1′-(6-((cyclopropylmethyl)thio)pyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(500 mg, 1.07 mmol) in DCM (10.0 mL) was added TFA (1.50 mL, 20.2 mmol)at 25° C., and the mixture was stirred at 25° C. for 16 h The mixturewas then adjusted the pH to 7˜8 with saturated NaHCO₃ solution andextracted with DCM (20.0 mL×3). The organic layer was washed with brine(20.0 mL×2), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.2% FA)-ACN]; B %: 10%-40%, 11 min) to give(S)-1′-(6-((cyclopropylmethyl)thio)pyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amineformate (60.7 mg, 141 umol, 13% yield, FA) as a yellow solid. LC-MS(ESI⁺) m/z: 366.3 (M+H)⁺; ¹H NMR (400 MHz DMSO-d₆): δ 8.26 (s, 1H), 8.19(d, J=3.0 Hz, 1H), 7.38 (t, J=3.6 Hz, 1H), 7.30 (dd, J=3.0, 8.8 Hz, 1H),7.23-7.19 (m, 3H), 7.13 (d, J=8.8 Hz, 1H), 4.01 (s, 1H), 3.56 (br d,J=12.6 Hz, 2H), 3.06-2.99 (m, 3H), 2.94-2.83 (m, 2H), 2.69 (d, J=16.2Hz, 1H), 1.91-1.72 (m, 2H), 1.50 (br d, J=13.2 Hz, 1H), 1.27 (br d,J=11.4 Hz, 1H), 1.11-0.99 (m, 1H), 0.53-0.46 (m, 2H), 0.28-0.20 (m, 2H).

Example 273: Synthesis of(R)-1′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine

(R)-1′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-aminewas synthesized as described above for Example 272, coupling sodium(R)-5-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazine-2-thiolate(Intermediate ES) and (bromomethyl)cyclopropane in Step a.Characterization of(R)-1′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine:LC-MS (ESI⁺) m/z: 369.2 (M+H)⁺; ¹H NMR (400 MHz MeOD-d₄): δ 8.45 (s,1H), 8.21 (d, J=1.4 Hz, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.47 (d, J=7.6 Hz,1H), 7.35-7.31 (m, 1H), 7.02-6.98 (m, 1H), 6.92 (d, J=8.0 Hz, 1H),4.43-4.40 (m, 2H), 4.23 (br d, J=13.2 Hz, 1H), 3.45-3.39 (m, 2H), 2.95(d, J=7.2 Hz, 2H), 2.05-2.01 (m, 2H), 1.85-1.81 (m, 2H), 1.05-1.02 (m,1H), 0.54-0.51 (m, 2H), 0.21-0.20 (m, 2H).

Example 274: Synthesis of(1′R,2r,3R,5′S)-8′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-amine

(1′R,2r,3R,5′S)-8′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-aminewas synthesized as described above for Example 272, coupling sodium5-((1′R,2r,3R,5′S)-3-((tert-butoxycarbonyl)amino)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-8′-yl)pyrazine-2-thiolate(Intermediate EU) and (bromomethyl)cyclopropane in Step a.Characterization of(1′R,2r,3R,5′S)-8′-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-3H-8′-azaspiro[benzofuran-2,3′-bicyclo[3.2.1]octan]-3-amine:LC-MS (ESI⁺) m/z: 378.1 (M−NH₂)⁺; ¹H NMR (400 MHz DMSO-d6): δ 8.20-8.19(m, 2H), 8.09 (s, 1H), 7.24 (d, J=7.2 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H),6.84 (t, J=7.2 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 4.66 (s, 1H), 4.58 (s,1H), 3.85 (s, 1H), 2.96 (d, J=7.2 Hz, 2H), 2.30 (d, J=7.2 Hz, 2H),2.26-2.22 (m, 1H), 1.97-1.92 (m, 3H), 1.74 (d, J=14.8 Hz, 1H), 1.62 (d,15.2 Hz, 1H), 1.04-1.01 (m, 1H), 0.50 (d, J=7.6 Hz, 2H), 0.21 (d, J=4.8Hz, 2H).

Examples 275, 276, & 277: Syntheses of (1s, 3′S,4R)-4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine,(1s, 3′R,4S)-4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amineand (1r,4r)-4-(5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-amine

Step a:

A mixture of4-(5-sulfanylpyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(137.0 mg, 441 μmol, Intermediate EZ), 2,3,4-trichloropyridine (120.0mg, 661 μmol) and TEA (304 μL, 2.20 mmol) in DMF (5.00 mL) was stirredat 70° C. for 12 hour under N₂. The reaction mixture was then dilutedwith EtOAc (100 mL), washed with H₂O (20 mL×3), brine (40 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (12 g column,EtOAc in petroleum ether from 0%˜20%) to give4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(200.0 mg, 99% yield) as a colorless oil. LC-MS (ESI+) m/z: 456.0(M+H)⁺.

Step b:

To a solution of4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(200 mg, 438 μmol) and Ti(OEt)₄ (899 μL, 4.37 mmol) in 2-Me-THF (1.00mL) was added (R)-2-methylpropane-2-sulfinamide (212.0 mg, 1.75 mmol).The reaction mixture was stirred at 95° C. for 48 h under N₂. Themixture was then cooled to rt and used in the next step directly. LC-MS(ESI⁺) m/z: 559.1, 561.0 (M+H)⁺.

Step c:

To the mixture of(R)—N-(4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-ylidene)-2-methylpropane-2-sulfinamide(240 mg, 428 μmol) in 2-Me-THF (5.00 mL) was added NaBH₄ (32.3 mg, 856μmol) at 20° C. The mixture was stirred at 20° C. for 1 hour. Thereaction was then quenched with MeOH (1 mL). The mixture was dilutedwith EtOAc (50 mL) and H₂O (20 mL) and the mixture was stirred at 25° C.for 5 min, where white solid formed. The mixture was filtered and thepartitioned layers of the filtrate were separated. The aqueous layer wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (petroleum ether:ethyl acetate=100:0 to 100:60) andprep-TLC (petroleum ether/ethyl acetate=1:1) to afford two products(R)—N-((1s,4S)-4-(5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamideand (R)—N-((1r,4R)-4-(5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide.The major product (R)—N-((1s,4S)-4-(5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(40.0 mg, 71.2 μmol) was obtained as a colorless oil, LC-MS (ESI⁺) m/z:561.1 (M+H)⁺. The product (R)—N-((1r,4R)-4-(5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(40.0 mg, 16% yield) was obtained as a colorless oil, LC-MS (ESI⁺) m/z:560.9 (M+H)⁺. The absolute configuration of the diastereomers wasarbitrarily assigned.

Step d:

(R)-2-Methyl-N-[(1s,4s)-4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(40.0 mg, 71.2 μmol) was dissolved in HCl/MeOH (2 mL, 4 M). The mixturewas stirred at 25° C. for 1 hour. Then the mixture was concentrated andwas purified by prep-HPLC (HCl) to afford two diastereoisomers. Theabsolute configuration of the diastereomers was arbitrarily assigned.The product (1s, 3′S,4R)-4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (11.2 mg, 22.6 μmol, HCl salt, 32% yield) was obtained asa white solid. LC-MS (ESI+) m/z: 439.9 (M−NH₂)⁺; ¹H NMR (400 MHz, CD₃OD)δ 8.79 (d, J=1.3 Hz, 1H), 8.68 (d, J=1.3 Hz, 1H), 8.14 (d, J=5.3 Hz,1H), 7.52 (d, J=7.4 Hz, 1H), 7.46-7.29 (m, 3H), 7.13 (d, J=5.4 Hz, 1H),4.37 (s, 1H), 3.16 (d, J=6.3 Hz, 2H), 3.05-2.91 (m, 1H), 2.07 (br d,J=3.1 Hz, 1H), 2.02-1.70 (m, 7H). The product (1s, 3′R,4S)-4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (1.0 mg, HCl salt, 3% yield) as a white solid. LC-MS(ESI+) m/z: 439.9 (M−NH₂)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.83-8.77 (m, 1H),8.71-8.59 (m, 1H), 8.18-8.11 (m, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.45-7.31(m, 3H), 7.13 (d, J=5.3 Hz, 1H), 4.36 (s, 1H), 3.25-3.09 (m, 2H),3.03-2.88 (m, 1H), 2.14-2.04 (m, 1H), 2.00-1.72 (m, 7H). SFC: e.e.=100%, Column: Chiralpak AS-3 100×4.6 mm I.D., 3 um. Mobile phase: A:CO₂, B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 4 min andhold 40% for 2.5 min, then 5% of B for 1.5 min Flow rate: 2.8 mL/min.Column temp.: 35° C. ABPR: 1500 psi.

Step e:

(R)-2-methyl-N-[(1r,4r)-4-{5-[(2,3-dichloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(20.0 mg, 35.6 μmol) was dissolved in HCl/MeOH (2.00 mL, 4 M). Themixture was stirred at 25° C. for 1 hour. The reaction mixture wasconcentrated and purified by prep-HPLC (HCl) to afford (1r,4r)-4-(5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-aminehydrochloride (4.0 mg, 23% yield) as a white solid. The absoluteconfiguration was arbitrarily assigned. LC-MS (ESI+) m/z: 440.0(M−NH₂)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.72-8.64 (m, 1H),8.20-8.09 (m, 1H), 7.60-7.48 (m, 1H), 7.46-7.29 (m, 3H), 7.19-7.08 (m,1H), 4.69 (s, 0.60H), 4.36 (s, 0.36H), 3.28-3.12 (m, 1H), 3.11-2.92 (m,1H), 2.79 (d, J=16.3 Hz, 1H), 2.16-1.54 (m, 8H). SFC: Column: ChiralcelOJ-3 100×4.6 mm I.D., 3 um. Mobile phase: A: CO₂, B: ethanol (0.05%DEA). Gradient: from 5% to 40% of B in 4 min and hold 40% for 2.5 min,then 5% of B for 1.5 min Flow rate: 2.8 mL/min. Column temp.: 35° C.ABPR: 1500 psi.

Example 278: Synthesis of(3R)-6-fluoro-1′-[5-methyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine

Step a:

A mixture of tert-butylN-[(3R)-6-fluoro-1′-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(1.3.0 g, 2.0 mmol, Intermediate FJ), piperidine (546.0 μL, 6.0 mmol),Cs₂CO₃ (1.95 g, 6.0 mmol) and XantPhos-Pd-G4 (191.0 mg, 199.0 μmol) intoluene (30.0 mL) was stirred at 100° C. for 12 hours under N₂atmosphere. The mixture was then concentrated in vacuo to give aresidue, which was purified by silica gel chromatography (ethyl acetatein petroleum ether=0% to 35%) to afford tert-butylN-[(3R)-6-fluoro-1′-[1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(510.0 mg, 43% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 608.1 (M+H)⁺.

Step b:

To a mixture of tert-butylN-[(3R)-6-fluoro-1′-[1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(510.0 mg, 839.0 μmol) in MeCN (10.0 mL) and AcOH (10.0 mL) was addedNBS (221.0 mg, 1.3 mmol), and the resulting mixture was stirred at 15°C. for 1 hour. The mixture was then concentrated in vacuo to give aresidue, which was purified by silica gel chromatography (ethyl acetatein petroleum ether=0% to 25%) to afford tert-butylN-[(3R)-1′-[5-bromo-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(330.0 mg, 57% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 686.1 (M+H)⁺.

Step c:

A mixture of tert-butylN-[(3R)-1′-[5-bromo-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(330.0 mg, 480.0 μmol), methylboronic acid (143.0 mg, 2.4 mmol), K₂CO₃(165.0 mg, 1.2 mmol) and Pd(dppf)Cl₂ (35.1 mg, 48.0 μmol) in 1,4-dioxane(15.0 mL) and H₂O (5.0 mL) was stirred at 90° C. for 12 hours under N₂atmosphere. The mixture was then concentrated in vacuo to give aresidue, which was purified by silica gel chromatography (ethyl acetatein petroleum ether=0% to 25%) to afford tert-butylN-[(3R)-6-fluoro-1′-[5-methyl-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 67% yield) as a yellow solid. LC-MS (ESI⁺) m/z 622.2 (M+H)⁺.

Step d:

A mixture of tert-butylN-[(3R)-6-fluoro-1′-[5-methyl-1-(oxan-2-yl)-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]carbamate(200.0 mg, 321.0 μmol) in HCl/MeOH (4M, 10.0 mL) was stirred at 15° C.for 1 hour. The mixture was then concentrated under reduced pressure togive a residue, which was purified by prep-HPLC (HCl) to afford(3R)-6-fluoro-1′-[5-methyl-3-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride (102.1 mg, 67% yield) as a yellow solid. LC-MS (ESI+) m/z:438.1 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ7.61-7.58 (m, 1H), 6.86-6.79 (m,2H), 4.73 (s, 1H), 4.24-4.15 (m, 1H), 4.08-3.90 (m, 5H), 3.56-3.43 (m,2H), 2.68 (s, 3H), 2.40-2.32 (m, 1H), 2.19-1.96 (m, 3H), 1.87-1.74 (m,6H).

Examples 279 & 280: Syntheses of(1s,3′S,4R)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amineand(1s,1′R,4S)-4-(6-((2,3-dichloropyridin-4-yl)thio)pyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-amine

Step a:

A mixture of(1s,4s)-4-(6-sulfanylpyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(312.0 mg, 1.0 mmol, Intermediate FS), 2,3,4-trichloropyridine (273.0mg, 1.5 mmol, CAS #55934-02-6) and TEA (693 μL, 5.0 mmol) in DMF (10 mL)was stirred at 70° C. for 14 hours under N₂. The reaction mixture wasthen diluted with EtOAc (80 mL), washed with H₂O (50 mL×3) and brine (40mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash silica gel chromatography (20 g column,EtOAc in petroleum ether from 0%˜30%) to give(1s,4s)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(215.0 mg, 0.5 mmol, 47% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 454.9(M+H)⁺.

Step b:

To a solution of(1s,4s)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(210.0 mg, 0.5 mmol) and Ti(OEt)₄ (945 μL, 4.6 mmol) in 2-Me-THF (1 mL)was added (R)-2-methylpropane-2-sulfinamide (558.0 mg, 4.6 mmol). Thereaction mixture was stirred at 95° C. for 64 hours under N₂. Themixture was then cooled to rt and used in the next step directly.

Step c:

To a mixture of(R)-2-methyl-N-[(1s,4s)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-ylidene]propane-2-sulfinamide(257.0 mg, 0.5 mmol) in 2-Me-THF (5 mL) was added NaBH₄ (34.7 mg, 0.9mmol) at 20° C., and the mixture was stirred at 20° C. for 1 hour. Thereaction was then quenched with MeOH (1 mL) and the mixture was dilutedwith EtOAc (50 mL) and H₂O (20 mL). The mixture was stirred at 25° C.for 5 min, where precipitate formed. The mixture was filtered and thepartitioned layers of the filtrate were separated. The aqueous layer wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (petroleum ether:ethyl acetate=100:0 to 100:50) toafford(R)-2-methyl-N-[(1s,4s)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(110.0 mg, 0.2 mmol, 43% yield). LC-MS (ESI+) m/z: 560.0 (M+H)⁺.

Step d:

(R)-2-Methyl-N-[(1s,4s)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(110.0 mg, 0.2 mmol) was separated by SFC (Column: Chiralpak AD-3 50×4.6mm I.D., 3 um. Mobile phase: A: C02; B: ethanol (0.05% DEA). Isocratic:40% B. Flow rate: 4 mL/min. Column temp.: 35° C. ABPR: 1500 psi) to give(R)-2-methyl-N-[(1s,3′S,4R)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(65.0 mg, 0.1 mmol) was as a yellow solid and(R)-2-methyl-N-[(1s,3′R,4S)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(10.0 mg, 0.02 mmol) as a yellow solid.

Step e:

A mixture of(R)-2-methyl-N-[(1s,3′S,4R)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(65.0 mg, 0.1 mmol) in HCl/MeOH (5 mL, 4 M) was stirred at 25° C. for 15min. The reaction mixture was then concentrated, and the residue waspurified by prep-HPLC (HCl) to give(1s,3′S,4R)-4-{6-[(2,3-dichloropyridin-4-yl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (25.5 mg, 45% yield) as a white solid. LC-MS (ESI+) m/z:439.0 (M−NH₂)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.94 (br s, 1H), 8.49 (br d,J=8.0 Hz, 1H), 8.21 (br d, J=5.2 Hz, 1H), 8.04 (br d, J=8.0 Hz, 1H),7.58 (d, J=7.2 Hz, 1H), 7.42-7.30 (m, 3H), 7.13 (br d, J=4.8 Hz, 1H),4.83 (s, 1H), 3.24 (d, J=16.4 Hz, 1H), 3.00 (br s, 1H), 2.73 (d, J=16.0Hz, 1H), 2.10-1.90 (m, 6H), 1.71-1.61 (m, 2H). SFC: e.e. =99%,R_(t)=2.169 min. Column: Chiralpak AD-3 50×4.6 mm I.D., 3 um. Mobilephase: A: CO₂, B: ethanol (0.05% DEA). Isocratic: 60% B. Flow rate: 3mL/min. Column temp.: 35° C. ABPR: 1500 psi.

Step f:

A mixture of(R)—N-((1s,1′R,4S)-4-(6-((2,3-dichloropyridin-4-yl)thio)pyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(10.0 mg, 0.02 mmol) in HCl/MeOH (2 mL, 4 M) was stirred at 15° C. for15 min. The reaction mixture was then concentrated. The residue waspurified by prep-HPLC (HCl) to give(1s,1′R,4S)-4-(6-((2,3-dichloropyridin-4-yl)thio)pyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-aminehydrochloride (1.9 mg, 0.004 mmol, 22% yield) as a white solid. LC-MS(ESI+) m/z: 439.0 (M−NH₂)⁺; ¹HNMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.09(d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.56 (d, J=7.2Hz, 1H), 7.42-7.35 (m, 3H), 6.95 (d, J=5.2 Hz, 1H), 4.76 (s, 1H), 3.24(d, J=16.4 Hz, 1H), 2.876 (br s, 1H), 2.75 (d, J=16.4 Hz, 1H), 2.08-1.82(m, 7H), 1.67-1.65 (m, 1H). SFC: e.e. =94%, R_(t)=0.937 min. Column:Chiralpak AD-3 50×4.6 mm I.D., 3 um. Mobile phase: A: CO₂. B: ethanol(0.05% DEA). Isocratic: 60% B. Flow rate: 3 mL/min. Column temp.: 35° C.ABPR: 1500 psi.

Examples 281 and 282: Syntheses of (1s, 3′S,4R)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amineand (1s, 3′R,4S)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine

Step a:

A mixture of(1s,4s)-4-(6-sulfanylpyridin-3-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(110.0 mg, 355 μmol, Intermediate FS), (bromomethyl)cyclopropane (143.0mg, 1.1 mmol) and TEA (179.0 mg, 1.7 mmol) in DMF (2.00 mL) was stirredat 70° C. for 12 hour under N₂. The reaction mixture was then dilutedwith EtOAc (100 mL), washed with H₂O (20 mL×3), brine (40 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (12 g column, EtOAc inpetroleum ether from 0%˜15%) to give(1s,4s)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(120.0 mg, 93% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 364.0 (M+H)⁺.

Step b:

To a solution of(1s,4s)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(120.0 mg, 330 μmol) and Ti(OEt)₄ (679 μL, 3.30 mmol) in 2-Me-THF (3.00mL) was added (R)-2-methylpropane-2-sulfinamide (159.0 mg, 1.3 mmol).The reaction mixture was then stirred at 95° C. for 96 h under N₂. Themixture was cooled to rt and used directly in the next step. LC-MS(ESI⁺) m/z: 467.2 (M+H)⁺.

Step c:

To a mixture of(R)-2-methyl-N-[(1s,4s)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-ylidene]propane-2-sulfinamide(150.0 mg, 321 μmol) in 2-Me-THF (5.00 mL) was added NaBH₄ (24.2 mg, 642μmol) at 20° C. and the reaction was stirred for 2 hours. The reactionwas then quenched with MeOH (1.00 mL) and the mixture was diluted withEtOAc (50 mL) and H₂O (20 mL). The mixture was stirred at 25° C. for 5min, where precipitate formed, and the mixture was filtered. Thepartitioned layers of the filtrate were separated and the aqueous layerwas extracted with ethyl acetate (20 mL×3). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:30) to afford (R)-2-methyl-N-[(1s,4s)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(40.0 mg, 27% yield) as a yellow solid. LC-MS (ESI⁺) m/z: 469.1 (M+H)⁺.

Step d:

(R)-2-Methyl-N-[(1s,4s)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(40.0 mg, 85.3 μmol) was dissolved in EtOAc (0.5 mL). Then HCl/EtOAc(0.5 mL, 4 M) was added and the mixture was stirred at 20° C. for 1hour, where yellow solid formed. The yellow solid was collected byfiltration to afford (1s,4s)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (20.0 mg, HCl salt, 58% yield) as a yellow solid. LC-MS(ESI⁺) m/z: 365.0 (M+H)⁺.

Step e:

(1s,4s)-4-{6-[(yclopropylmethyl)sulfanylC]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine(20.0 mg, 54.8 μmol, HCl salt) was separated by Chiral-SFC (DAICELCHIRALPAK AS (250 mm*30 mm, 10 um)) Mobile phase: 35% of EtOH (0.1%NH₃.H₂O) in CO₂, Flow rate: 80 mL/min) to give (1s, 3′S,4R)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine(3.10 mg, 16% yield) as a yellow solid (LC-MS (ESI+) m/z: 365.1 (M+H)⁺;¹HNMR (400 MHz, Methanol-d₄): δ 8.37-8.25 (m, 1H), 7.69-7.53 (m, 1H),7.41 (br d, J=6.0 Hz, 1H), 7.34-7.09 (m, 4H), 4.25 (s, 1H), 3.28-3.01(m, 3H), 2.69-2.43 (m, 2H), 2.23-2.04 (m, 1H), 1.94-1.58 (m, 6H),1.53-1.34 (m, 2H), 1.12 (m, 7.7, 12.0 Hz, 1H), 0.65-0.53 (m, 2H),0.34-0.25 (m, 2H); SFC: e.e. =100%, R_(t)=2.169 min. Column: ChiralpakAS-3 100×4.6 mm I.D., 3 um. Mobile phase: A: CO₂, B: ethanol (0.05%DEA). Gradient: from 5% to 40% of B in 4 min and hold 40% for 2.5 min,then 5% of B for 1.5 min Flow rate: 2.8 mL/min. Column temp.: 35° C.ABPR: 1500 psi) and (1s, 3′R,4S)-4-{6-[(cyclopropylmethyl)sulfanyl]pyridin-3-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine(3.1 mg, 16% yield) as a white solid (LC-MS (ESI⁺) m/z: 365.1 (M+H)⁺;¹HNMR (400 MHz, Methanol-d₄): δ 8.34 (d, J=2.1 Hz, 1H), 7.64 (dd, J=2.3,8.3 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.45-7.25 (m, 4H), 4.78 (s, 1H),3.28-3.04 (m, 3H), 2.79-2.62 (m, 2H), 2.10-1.90 (m, 2H), 1.84-1.54 (m,4H), 1.52-1.35 (m, 1H), 1.18-1.06 (m, 1H), 0.96-0.86 (m, 1H), 0.64-0.54(m, 2H), 0.38-0.26 (m, 2H)). The absolute configuration of thediastereomers was assigned arbitrarily.

Examples 283, 284, & 285: Syntheses of (1s, 3′S,4R)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine,(1s, 1′R,4S)-4-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-amineand (1r,4r)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-amine

Step a:

A mixture of4-(5-sulfanylpyrazin-2-yl)-14-(5-mercaptopyrazin-2-yl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one(137.0 mg, 441 μmol, Intermediate EZ), (bromomethyl)cyclopropane (178.0mg, 1.32 mmol) and TEA (304 μL, 2.20 mmol) in DMF (2.00 mL) was stirredat 70° C. for 12 hour under N₂. The reaction mixture was diluted withEtOAc (50 mL), washed with H₂O (20 mL×3), brine (20 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (EtOAc inpetroleum ether from 0%˜15%) to give-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one(160.0 mg, 438 μmol, 100% yield) as a yellow oil. LC-MS (ESI⁺) m/z:364.9 (M+H)⁺.

Step b:

To a solution of4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-one(160.0 mg, 438 μmol) and Ti(OEt)₄ (899 μL, 4.37 mmol) in 2-Me-THF (1.00mL) was added (R)-2-methylpropane-2-sulfinamide (212.0 mg, 1.75 mmol).The reaction mixture was stirred at 95° C. for 48 h under N₂. Themixture was then cooled to rt and used in the next step directly. LC-MS(ESI⁺) m/z: 468.2 (M+H)⁺.

Step c:

To a mixture of(R)—N-(4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-ylidene)-2-methylpropane-2-sulfinamide(200.0 mg, 427 μmol) in 2-Me-THF (5 mL) was added NaBH₄ (32.2 mg, 854μmol) at 20° C. The mixture was stirred at 20° C. for 1 hour. Thereaction was then quenched with MeOH (1 mL) and the mixture was dilutedwith EtOAc (50 mL) and H₂O (20 mL). The mixture was stirred at 25° C.for 5 min, where a precipitate formed and the mixture was filtered. Thepartitioned layers of the filtrate were separated and the aqueous layerwas extracted with ethyl acetate (20 mL×3). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue. The residue was purified by flashsilica gel chromatography (petroleum ether:ethyl acetate=100:0 to100:30) to afford (R)—N-((1S,4S)-4-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(60.0 mg, 30% yield) as the major product as a colorless oil. LC-MS(ESI⁺) m/z: 470.1 (M+H)⁺. Another product (30.0 mg) was further purifiedby prep-HPLC (HCOOH) to afford (R)—N-((1r,4R)-4-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(5.0 mg, 3% yield) as a white solid (5.0 mg, 2.5% yield). LC-MS (ESI⁺)m/z: 470.1 (M+H)⁺. The absolute configuration of the diastereomers wasarbitrarily assigned.

Step d:

(R)-2-Methyl-N-[(1s,4s)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(60.0 mg, 127 μmol) was separated by Chiral-SFC (DAICEL CHIRALCEL OD(250 mm*30 mm, 10 um) Mobile phase: 35% of EtOH (0.1% NH₃H₂O) in CO₂.Flow rate: 70 mL/min) to give (R)-2-methyl-N-[(1s, 3′S,4R)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(16.0 mg, 27% yield) as a white solid (LC-MS (ESI⁺) m/z: 470.1 (M+H)⁺)and (R)-2-methyl-N-[(1s, 3′R,4S)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(9.0 mg, 15% yield) was as a white solid (LC-MS (ESI⁺) m/z: 470.1(M+H)⁺).

Step e:

(R)-2-Methyl-N-[(1s, 3′S,4R)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(16.0 mg, 34.0 μmol) was dissolved in EtOAc (0.25 mL), then HCl/EtOAc(0.25 mL, 4 M) was added. The mixture was stirred at 20° C. for 0.5hour, where precipitate formed. The solid was collected by filtrationand was purified by prep-HPLC (HCl) to afford (1s, 3′S,4R)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (8.4 mg, HCl salt, 62% yield) as a yellow solid. LC-MS(ESI⁺) m/z: 349.1 (M−NH₂)⁺; ¹H NMR (400 MHz, CD₃OD) δ8.53-8.41 (m, 2H),7.51 (d, J=7.5 Hz, 1H), 7.44-7.28 (m, 3H), 4.35 (s, 1H), 3.23-3.09 (m,4H), 2.91-2.76 (m, 1H), 2.08-1.98 (m, 1H), 1.97-1.69 (m, 7H), 1.16 (dt,^(J)=4.7, 7.8 Hz, 1H), 0.69-0.54 (m, 2H), 0.38-0.29 (m, 2H). SFC: e.e.=100%, R_(t)=2.922 min. Column: Chiralpak AS-3 100×4.6 mm I.D., 3 um.Mobile phase: A: CO₂, B: ethanol (0.05% DEA). Gradient: from 5% to 40%of B in 4 min and hold 40% for 2.5 min, then 5% of B for 1.5 min Flowrate: 2.8 mL/min. Column temp.: 35° C. ABPR: 1500 psi. The absoluteconfiguration of the diastereomer was arbitrarily assigned.

Step f:

(R)—N-((1s, 1′R,4S)-4-(5-((Cyclopropylmethyl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-yl)-2-methylpropane-2-sulfinamide(9.0 mg, 19.1 μmol) was dissolved in EtOAc (0.25 mL), then HCl/EtOAc(0.25 mL, 4 M) was added and the mixture was stirred at 20° C. for 0.5hour, where a solid precipitate formed. The yellow solid was collectedby filtration to afford (1s, 1′R,4S)-4-(5-((cyclopropylmethyl)thio)pyrazin-2-yl)-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-aminehydrochloride (6.9 mg, HCl salt, 90% yield) as a yellow solid. LC-MS(ESI+) m/z: 349.0 (M−NH₂)⁺; ¹HNMR (400 MHz, CD₃OD) δ8.56-8.38 (m, 2H),7.54 (d, J=7.3 Hz, 1H), 7.43-7.28 (m, 3H), 4.69 (s, 1H), 3.26-3.10 (m,3H), 2.97-2.84 (m, 1H), 2.74 (d, J=16.3 Hz, 1H), 2.09-1.78 (m, 6H),1.75-1.51 (m, 2H), 1.20-1.07 (m, 1H), 0.64-0.52 (m, 2H), 0.36-0.25 (m,2H). SFC: e.e. =100%, R_(t)=2.827 min. Column: Chiralpak AS-3 100×4.6 mmI.D., 3 um. Mobile phase: A: CO₂, B: ethanol (0.05% DEA). Gradient: from5% to 40% of B in 4 min and hold 40% for 2.5 min, then 5% of B for 1.5min Flow rate: 2.8 mL/min. Column temp.: 35° C. ABPR: 1500 psi. Theabsolute configuration of the diastereomer was arbitrarily assigned.

Step g:

(R)-2-Methyl-N-[(1r,4r)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-yl]propane-2-sulfinamide(5.0 mg, 10.6 μmol) was added into HCl/MeOH (1 mL, 4M) and the mixturewas stirred at 25° C. for 1 h. The mixture was then concentrated and waspurified by prep-HPLC (HCl) to afford (1r,4r)-4-{5-[(cyclopropylmethyl)sulfanyl]pyrazin-2-yl}-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-3′-aminehydrochloride (2.2 mg, HCl salt, 52% yield) as a white solid as amixture of diastereomers. LC-MS (ESI⁺) m/z: 348.9 (M−NH₂)⁺; ¹HNMR (400MHz, CD₃OD) δ 8.56-8.38 (m, 2H), 7.54 (d, J=7.3 Hz, 1H), 7.43-7.28 (m,3H), 4.69 (s, 1H), 3.26-3.10 (m, 3H), 2.97-2.84 (m, 1H), 2.74 (d, J=16.3Hz, 1H), 2.09-1.78 (m, 6H), 1.75-1.51 (m, 2H), 1.20-1.07 (m, 1H),0.64-0.52 (m, 2H), 0.36-0.25 (m, 2H). SFC: R_(t)=3.453 min andR_(t)=2.443 min. Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um. Mobilephase: A: CO₂, B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in4 min and hold 40% for 2.5 min, then 5% of B for 1.5 min Flow rate: 2.8mL/min. Column temp.: 35° C. ABPR: 1500 psi. The absolute configurationof the diastereomer was arbitrarily assigned.

Example 286: Synthesis of(1S)-1′-[2-(2,6-dichlorophenyl)-1,3-thiazole-4-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

(R)—N—((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(352.0 mg, 1.15 mmol, synthesized via Step a of Example 120),2-bromo-1,3-thiazole-4-carboxylic acid (200 mg, 961 μmol), HATU (547 mg,1.44 mmol) and TEA (671 μL, 4.80 mmol) were placed into DMF (10 mL). Thereaction mixture was stirred at 25° C. for 12 hour. The mixture wasdiluted with EtOAc (100 mL) and the mixture was washed with H₂O (30mL×5), brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (ethyl acetate in petroleum ether=0% to 80%) toafford(R)—N—((S)-1′-(2-bromothiazole-4-carbonyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide(400 mg, 84% yield) as a yellow oil. LC-MS (ESI+) m/z: 498.0 (M+H)⁺.

Step b:

(S)—N-[(1S)-1′-(2-bromo-1,3-thiazole-4-carbonyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(200.0 mg, 402 μmol), bis(tri-tert-butylphosphine)palladium (20.5 mg,40.2 μmol), DIPEA (114.0 mg, 884 μmol) and (2,6-dichlorophenyl)boronicacid (92.0 mg, 482 μmol) were placed into dioxane/H₂O (10/0.6 mL). Thereaction mixture was evacuated and refilled 3 times using N₂ and thereaction mixture was stirred at 120° C. for 3 hours. The reactionmixture was then concentrated and H₂O (30 mL) was added, and thesolution was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (petroleum ether:ethylacetate=100:50 to 100:100 then EtOAc:MeOH=100:10) to afford(S)—N-[(1S)-1′-[2-(2,6-dichlorophenyl)-1,3-thiazole-4-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(27.0 mg, 12% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 584.0 (M+Na)⁺.

Step c:

The mixture of(S)—N-[(1S)-1′-[2-(2,6-dichlorophenyl)-1,3-thiazole-4-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(27.0 mg, 47.9 μmol) in HCl/MeOH (4 mL, 4 M) was stirred at 25° C. for0.5 hour. The combined reaction mixture was concentrated to give aresidue. The residue was dissolved in MeOH (5 mL), and the reactionmixture was adjusted pH=8-9 with solid Na₂CO₃. The mixture was filtered,and the filtrate was purified by pre-HPLC (basic condition) to afford(1S)-1′-[2-(2,6-dichlorophenyl)-1,3-thiazole-4-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(4.10 mg, 19% yield) as a white solid. LC-MS (ESI⁺) m/z: 458.0 (M+H)⁺.¹HNMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 7.64-7.49 (m, 3H), 7.37 (s, 1H),7.26-7.16 (m, 3H), 4.49 (m, 1H), 4.18 (m, 1H), 3.98 (m, 1H), 3.55-3.34(m, 2H), 3.16 (s, 1H), 2.82 (s, 1H), 2.12-1.77 (m, 2H), 1.76-1.22 (m,3H).

Example 287: Synthesis of(1S)-1′-[1-(3-methoxyphenyl)-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

1-(3-Methoxyphenyl)-1H-pyrazole-3-carboxylic acid (95.0 mg, 0.44 mmol,Intermediate FX), TEA (303 μL, 2.17 mmol) and HATU (248.0 mg, 0.65 mmol)were placed into DMF (5 mL) and the reaction mixture was stirred at 25°C. for 1 hour. Then(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(173 mg, 0.57 mmol, synthesized via Step a of Example 120) was added andthe resulting mixture was stirred at 25° C. for 12 hours. The mixturewas diluted with EtOAc (50 mL). The mixture was washed with H₂O (30mL×2), brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by silica gelchromatography (ethyl acetate in petroleum ether=0% to 100% to afford(R)—N-[(3S)-1′-[1-(3-methoxyphenyl)-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(126.0 mg, 57% yield) as yellow oil. LC-MS (ESI+) m/z: 507.1 (M+H)⁺.

Step b:

(R)—N-[(3S)-1′-[1-(3-Methoxyphenyl)-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(126 mg, 0.2486 mmol) was dissolved in HCl/MeOH (2 mL, 4 M) and stirredat 25° C. for 1 hour. The mixture was then concentrated to give aresidue which was purified by prep-HPLC (HCl) to afford(1S)-1′-[1-(3-methoxyphenyl)-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (43.2 mg, 34% yield) as a white solid. LC-MS (ESI⁺) m/z:403.1 (M+H)⁺; ¹HNMR (400 MHz, DMSO-d₆) δ=8.48˜8.51 (m, 4H), 7.62˜7.64(m, 1H), 7.40˜7.44 (m, 3H), 7.27˜7.38 (m, 3H), 6.92˜6.98 (m, 1H),6.79˜6.80 (m, 1H), 4.30˜4.60 (m, 3H), 3.86 (s, 3H), 3.22˜3.40 (m, 1H),2.99˜3.04 (m, 3H), 1.78˜1.89 (m, 2H), 1.54˜1.65 (m, 2H).

Example 288: Synthesis of(1S)-1′-[1-(3-methoxyphenyl)-1H-pyrazole-5-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

The compound of 1-(3-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (28.1mg, 0.13 mmol, Intermediate FY), TEA (90.1 μL, 0.64 mmol) and HATU (73.3mg, 0.19 mmol) were placed into DMF (2 mL). The reaction mixture wasstirred at 25° C. for 1 hour. Then(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(51.2 mg, 0.1673 mmol, synthesized via Step a of Example 120) was added,and the resulting mixture was stirred at 25° C. for 12 hour. The mixturewas then diluted with EtOAc (50 mL). The mixture was washed with H₂O (30mL×2), brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by prep-TLC(ethyl acetate:petroleum ether=1:0) to afford(R)—N-[(3S)-1′-[1-(3-methoxyphenyl)-1H-pyrazole-5-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(37.0 mg, 57% yield) as a yellow oil. LC-MS (ESI+) m/z: 507.1 (M+H)⁺.

Step b:

A solution of tert-butylN-[(1S)-1′-[1-(3-methoxyphenyl)-1H-pyrazole-5-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]carbamate(37.0 mg, 73.6 μmol) in HCl/MeOH (5 mL, 4 M) was stirred at 25° C. for 1hour. The reaction mixture was then concentrated under reduced pressureand purified by prep-HPLC (NH₃.H₂O) to afford(1S)-1′-[1-(3-methoxyphenyl)-1H-pyrazole-5-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine(14.7 mg, 50% yield) as a white solid. LC-MS (ESI⁺) m/z: 403.2 (M+H)⁺;¹H NMR (400 MHz, DMSO-d₆) δ=7.76˜7.78 (m, 1H), 7.41˜7.46 (m, 1H),7.26˜7.29 (m, 1H), 7.14˜7.18 (m, 3H), 6.99˜7.07 (m, 3H), 6.64˜6.67 (m,1H), 4.17˜4.24 (m, 1H), 3.72˜3.80 (m, 4H), 2.99˜3.17 (m, 3H), 2.89˜2.96(m, 1H), 2.52˜2.56 (m, 1H), 1.44˜1.63 (m, 2H), 1.19˜1.32 (m, 1H),0.82˜1.10 (m, 1H).

Example 289: Synthesis of(1S)-1′-[1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of 1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxylicacid (140.0 mg, 587.0 μmol, Intermediate FZ),(R)—N-[(1S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(307.0 mg, 704.0 μmol, synthesized via Step a of Example 120), HATU(334.0 mg, 880.0 μmol) and TEA (242.0 μL, 1.8 mmol) in DMF (10.0 mL) wasstirred at 20° C. for 12 hours. The mixture was diluted with ethylacetate (50.0 mL), and washed with H₂O (30.0 mL×2). The organic phasewas washed with brine (15.0 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (methanol in dichloromethane=0% to 10%) toafford(R)—N-[(1S)-1′-[1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(250 mg, 81% yield) as a white solid. LC-MS (ESI⁺) m/z 527.2 (M+H)⁺.

Step b:

A mixture of(R)—N-[(1S)-1′-[1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfinamide(240.0 mg, 455.0 μmol) in HCl/MeOH (4M, 5.0 mL) was stirred at 20° C.for 0.5 hours. The mixture was then concentrated under reduced pressureto give a residue, which was purified by prep-HPLC (HCl) to afford(1S)-1′-[1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (151 mg, 73% yield) as a white solid. LC-MS (ESI⁺) m/z:406.0 (M−NH₂)⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 7.64-7.17 (m, 7H), 6.60(d, J=4.0 Hz, 1H), 4.64-4.37 (m, 3H), 3.60-3.50 (m, 1H), 3.28-3.15 (m,3H), 2.25 (s, 3H), 1.91-1.57 (m, 4H).

Example 290 and 291: Syntheses of(S)-1-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-(4-fluorophenyl)propan-1-oneand(R)-1-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-(4-fluorophenyl)propan-1-one

Step a:

(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(652.0 mg, 2.13 mmol, synthesized via Step a of Example 120),2-(4-fluorophenyl)propanoic acid (300.0 mg, 1.78 mmol), HATU (1.01 g,2.67 mmol) and TEA (1.24 mL, 8.90 mmol) were placed into DMF (10 mL).The reaction mixture was stirred at 25° C. for 1 hour. The mixture wasdiluted with EtOAc (100 mL) and the mixture was washed with H₂O (30mL×5), brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (ethyl acetate in petroleum ether=0% to 75% to afford(R)—N-[(3S)-1′-[2-(4-fluorophenyl)propanoyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(370 mg, 46% yield) as yellow oil. LC-MS (ESI⁺) m/z: 457.1 (M+H)⁺.

Step b:

The mixture of(R)—N-[(3S)-1′-[2-(4-fluorophenyl)propanoyl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(180.0 mg, 394 μmol) in HCl/MeOH (5 mL, 4 M) was stirred at 25° C. for0.5 hour. The combined reaction mixture was then concentrated to give aresidue. The residue was dissolved in MeOH (5.00 mL), and the reactionmixture was adjusted pH=8-9 with solid Na₂CO₃. The mixture was filtered,and the filtrate was concentrated to give1-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-2-(4-fluorophenyl)propan-1-one(110 mg, 80% yield) as a white solid. LC-MS (ESI⁺) m/z: 336.0 (M−NH₂)⁺.

Step c:

1-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-(4-fluorophenyl)propan-1-one(110 mg, 312 μmol) was separated by Chiral-SFC (DAICEL CHIRALPAK AD (250mm*30 mm, 10 um)), mobile phase: 45%% NH₃.H₂O/IPA in CO₂, flow rate: 80mL/min) to give(S)-1-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-(4-fluorophenyl)propan-1-one(37.8 mg, 107 μmol, 35% yield, R_(t)=4.004 min) as a white solid (LC-MS(ESI⁺) m/z: 336.0 (M−NH₂)⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 7.39-7.27(m, 3H), 7.18 (m, 3H), 7.12-7.03 (m, 2H), 4.44-4.24 (m, 1H), 4.15 (m,1H), 3.98-3.68 (m, 2H), 3.44-3.34 (m, 1H), 3.16-2.94 (m, 2H), 2.81-2.60(m, 1H), 1.78-1.63 (m, 1H), 1.51 (s, 1H), 1.40 (m, 5H); SFC: e.e. =100%,R_(t)=3.988 min) and(R)-1-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-(4-fluorophenyl)propan-1-one(40.9 mg, 116 μmol, 38% yield, R_(t)=4.926 min) as a white solid (LC-MS(ESI⁺) m/z: 336.0 (M−NH₂)⁺; 7.40-7.24 (m, 3H), 7.17 (s, 3H), 7.12-7.01(m, 2H), 4.45-4.25 (m, 1H), 4.16 (m, 1H), 3.95-3.78 (m, 2H), 3.39-3.33(m, 1H), 3.11-2.97 (m, 2H), 2.79-2.54 (m, 1H), 1.84-1.20 (m, 7H); SFC:e.e. =99.5%, R_(t)=4.898 min). Column: Chiralpak AD-3 100×4.6 mm I.D., 3um. Mobile phase: A: CO₂ B: iso-propanol (0.05% DEA). Gradient: from 5%to 40% of B in 4 min and hold 40% for 2.5 min, then 5% of B for 1.5 min.Flow rate: 2.8 mL/min. Column temp.: 35° C. The absolute configurationof the diastereomers was arbitrarily assigned.

Example 292: Synthesis of(3S)-1′-(2-phenoxybenzoyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

(R)—N-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(171.0 mg, 559 μmol, synthesized via Step a of Example 120),2-phenoxybenzoic acid (100.0 mg, 466 μmol, CAS #2243-42-7), HATU (265.0mg, 699 μmol) and TEA (325 μL, 2.3 mmol) were placed into DMF (10.00mL). The reaction mixture was stirred at 25° C. for 12 hours. Themixture was diluted with EtOAc (100 mL) and was washed with H₂O (30mL×5), brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by flash silicagel chromatography (ethyl acetate in petroleum ether=0% to 75% to afford(R)-2-methyl-N-[(3S)-1′-(2-phenoxybenzoyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]propane-2-sulfinamide(190.0 mg, 81% yield) as a yellow oil. LC-MS (ESI⁺) m/z: 525.1 (M+Na)⁺.

Step b:

A mixture of(R)-2-methyl-N-[(3S)-1′-(2-phenoxybenzoyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]propane-2-sulfinamide(188.0 mg, 374 μmol) in HCl/MeOH (5.00 mL, 4 M) was stirred at 25° C.for 0.5 hour. The reaction mixture was concentrated to give a residue.The residue was purified by prep-HPLC (HCl) to give(3S)-1′-(2-phenoxybenzoyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (63.2 mg, 39% yield) as a white solid. LC-MS (ESI⁺) m/z:399.1 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 8.71-8.38 (m, 3H), 7.64-7.56(m, 1H), 7.48-7.15 (m, 9H), 7.10-7.00 (m, 2H), 6.90 (br d, J=8.0 Hz,1H), 4.47-4.02 (m, 2H), 3.54-3.45 (m, 1H), 3.33-3.09 (m, 3H), 3.05-2.83(m, 1H), 1.94-1.60 (m, 2H), 1.57-1.26 (m, 2H).

Example 293: Synthesis of(S)-1′-(5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

Step a:

A mixture of (S)-tert-butyl(1′-(5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate(100.0 mg, 181.0 μmol, synthesized via Steps a-b of Intermediate FH) inHCl/MeOH (4M, 10.0 mL) was stirred at 20° C. for 1 hour. The mixture wasconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (HCl) to afford(S)-1′-(5-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-aminehydrochloride (20.6 mg, 30% yield) as a white solid. LC-MS (ESI⁺) m/z:339.0 (M+H)⁺; ¹H NMR (400 MHz, Methanol-d₄): δ 7.55 (d, J=7.6 Hz, 1H),7.44-7.35 (m, 4H), 4.49 (s, 1H), 4.05-4.00 (m, 1H), 3.91-3.86 (m, 1H),3.64-3.54 (m, 2H), 3.27-3.18 (m, 2H), 2.49 (d, J=1.2 Hz, 3H), 2.08-1.84(m, 3H), 1.75-1.69 (m, 1H).

Example 294: Synthesis of(3S)-1′-{3′,6′-dimethyl-[3,4′-bipyridin]-2′-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine

Step a:

A mixture of 2′-chloro-3′,6′-dimethyl-3,4′-bipyridine (190.0 mg, 0.9mmol, Intermediate GA), tert-butylN-[(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate (338.0mg, 1.1 mmol, Intermediate EF), RuPhos-Pd-G4 (73.8 mg, 0.08 mmol, CAS#1599466-85-9), RuPhos (81.0 mg, 0.2 mmol, CAS #787618-22-8), Cs₂CO₃(852.0 mg, 2.6 mmol) and NaI (194.0 mg, 1.3 mmol) were added in toluene(6 mL). The reaction mixture was evacuated and refilled 3 times usingN₂, and the reaction mixture was stirred at 120° C. for 12 hours. Thereaction mixture was then poured into H₂O (40 mL) and extracted withEtOAc (80 mL×2). The combined organic layers were washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (10 g, MeOH in DCM from 0% to 10%) to givetert-butylN-[(3S)-1′-{3′,6′-dimethyl-[3,4′-bipyridin]-2′-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(134.0 mg, 0.3 mmol, 32% yield) as a brown oil. LC-MS (ESI⁺) m/z: 485.1(M+H)⁺.

Step b:

A mixture of tert-butylN-[(3S)-1′-{3′,6′-dimethyl-[3,4′-bipyridin]-2′-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]carbamate(120.0 mg, 0.2 mmol) in HCl/MeOH (5 mL, 4 M) was stirred at 15° C. for 1hour. The mixture was then concentrated and the residue was purified byprep-HPLC (HCl condition) to give(3S)-1′-{3′,6′-dimethyl-[3,4′-bipyridin]-2′-yl}-1,3-dihydrospiro[indene-2,4′-piperidin]-3-aminehydrochloride (44.9 mg, 0.11 mmol, 43% yield) as a yellow solid. LC-MS(ESI⁺) m/z: 385.1 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD): δ 9.38 (m, 1H), 9.14(d, J=5.6 Hz, 1H), 8.98 (d, J=8.0 Hz, 1H), 8.35 (t, J=6.4 Hz, 1H),7.59-7.54 (m, 1H), 7.42-7.28 (m, 4H), 4.56 (s, 1H), 4.00-3.82 (m, 2H),3.57-3.47 (m, 2H), 3.25-3.19 (m, 2H), 2.70 (s, 3H), 2.32 (s, 3H),2.14-1.72 (m, 4H).

SHP2 Allosteric Inhibition Assay.

SHP2 is allosterically activated through binding ofbis-tyrosyl-phorphorylated peptides to its Src Homology 2 (SH2) domains.The latter activation step leads to the release of the auto-inhibitoryinterface of SHP2, which in turn renders the SHP2 protein tyrosinephosphatase (PTP) active and available for substrate recognition andreaction catalysis. The catalytic activity of SHP2 is monitored usingthe surrogate substrate DiFMUP in a prompt fluorescence assay format.

More specifically, the phosphatase reactions re performed at roomtemperature in 96-well black polystyrene plate, flat bottom, low flange,non-binding surface (Corning, Cat #3575) using a final reaction volumeof 50 μl and the following assay buffer conditions: 60 mM HEPES, pH 7.2,75 mM NaCl, 75 mM KCl, 1 mM EDTA 0.005% Brij-35, 5 mM DTT.

The inhibition of SHP2 by compounds of the disclosure (concentrationsvarying from 0.003-100 μM) is monitored using an assay in which 0.25 nMof SHP2 is incubated with of 0.5 μM of peptide IRSl_pY1172(dPEG8)pY222(sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide). After 30-60minutes incubation at 25° C., the surrogate substrate DiFMUP(Invitrogen, cat #D6567, 100 μM final) is added to the reaction and theconversion of DiFMIP to 6,8-difluoro-7-hydroxyl-4-methylcoumarin (DiFMU)is monitored continuously for 10 minutes with excitation at 355 nm andemission at 460 nm using a microplate reader (PolarStar, BMG). Theinhibitor dose response curves are analyzed using normalized IC₅₀regression curve fitting with control based normalization.

Results of the SHP2 allosteric inhibition assay are depicted in thetable below. Compounds designated as “A” have an IC₅₀ value less than orequal to 50 nM; compounds designated as “B” have an IC₅₀ value greaterthan 50 nM but less than or equal to 1 uM; compounds designated as “C”have an IC₅₀ value greater than 1 uM but less than or equal to 10 uM;and compounds designated as “D” have an IC₅₀ value greater than 10 uM.

TABLE 2 Results of SHP2 allsosteric inhibition assay. Example SHP2 IC₅₀1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 B 16 C17 A 18 A 19 B 20 A 21 A 22 A 23 C 24 A 25 A 26 A 27 A 28 A 29 A 30 A 31A 32 A 33 A 34 A 35 A 36 A 37 A 38 A 39 A 40 D 41 A 42 A 43 A 44 A 45 A46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60A 61 A 62 A 63 B 64 A 65 A 66 B 67 A 68 A 69 A 70 B 71 A 72 A 73 A 74 A75 A 76 A 77 A 78 A 79 A 80 A 80 A 81 A 82 A 84 A 84 A 86 A 87 A 88 A 89A 90 B 91 C 92 A 93 A 94 A 95 A 96 A 97 B 98 B 99 A 100 B 101 B 102 A103 A 104 A 105 A 106 A 107 A 108 A 109 A 110 A 111 A 112 A 113 A 114 A115 A 116 C 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 A127 B 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 A 136 A 137 A 138 A139 A 140 A 141 A 142 A 143 A 144 A 145 A 146 A 147 A 148 A 149 A 150 B151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 A 159 A 160 A 161 A 162 D163 C 164 A 165 D 166 A 167 A 168 A 169 C 170 B 171 A 172 C 173 D 174 A175 C 176 D 177 A 178 D 179 A 180 C 181 C 182 D 183 D 184 B 185 C 186 A187 A 188 D 189 A 190 A 191 C 192 C 193 A 194 A 195 A 196 A 197 A 198 D199 A 200 A 201 A 202 A 203 A 204 A 205 B 206 A 207 C 208 C 209 C 210 D211 B 212 A 213 B 214 A 215 A 216 B 217 A 218 A 219 A 220 A 221 A 222 A223 A 224 B 225 D 226 A 227 D 228 D 229 A 230 C 231 D 232 A 233 A 234 A235 D 236 A 237 A 238 A 239 B 240 A 241 A 242 A 243 B 244 A 245 C 246 D247 C 248 A 249 A 250 A 251 D 252 A 253 A 254 D 255 A 256 A 257 A 258 A259 A 260 D 261 A 262 B 263 A 264 A 265 A 266 A 267 A 268 A 269 A 270 C271 A 272 A 273 A 274 C 275 C 276 A 277 B 278 A 279 A 280 A 281 B 282 A283 D 284 B 285 A 286 A 287 A 288 D 289 A 290 A 291 D 292 D 293 A 294 A

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety for all purposes as if each individualpublication or patent was specifically and individually incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject disclosure have beendiscussed, the above specification is illustrative and not restrictive.Many variations of the present disclosure will become apparent to thoseskilled in the art upon review of this specification. The full scope ofthe disclosure should be determined by reference to the claims, alongwith their full scope of equivalents, and the specification, along withsuch variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure.

What is claimed is: 1-65. (canceled)
 66. A method of treating aSHP2-mediated cancer, the method comprising administering to a humansubject having said cancer an effective amount of a compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 67. The method of claim66, wherein the SHP2-mediated cancer is chronic myelomonocytic leukemia,acute myeloid leukemia, breast cancer, non-small cell lung cancer(NSCLC), colorectal cancer (CRC), esophageal cancer, gastric cancer,squamous-cell carcinoma of the head and neck (SCCHN), or ovarian cancer.68. The method of claim 67, wherein the SHP2-mediated cancer is breastcancer and wherein the breast cancer is HER2-positive breast cancer,triple-negative breast cancer, ductal carcinoma, or invasive ductalcarcinoma.
 69. The method of claim 67, wherein the SHP2-mediated canceris NSCLC.
 70. The method of claim 67, wherein the SHP2-mediated canceris CRC.
 71. The method of claim 66, further comprising administration ofan effective amount of an antibody, an antibody-drug conjugate, animmunomodulator, or a histone deacetylase inhibitor.
 72. The method ofclaim 66, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 73. The method of claim66, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 74. The method of claim66, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 75. The method of claim66, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 76. A method of treatingSHP2-mediated Noonan syndrome, juvenile leukemia, or juvenilemyelomonocyic leukemia (JMML) in a human subject having Noonan syndrome,juvenile leukemia, or juvenile myelomonocyic leukemia (JMML), the methodcomprising administering to the subject an effective amount of acompound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 77. The method of claim76, wherein the method consists of treating SHP2-mediated Noonansyndrome.
 78. The method of claim 76, wherein the compound has theformula:

or a pharmaceutically acceptable salt thereof.
 79. The method of claim76, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 80. The method of claim76, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 81. A method ofinhibiting SHP2 phosphatase activity in a tumor cell, the methodcomprising contacting the cell with an effective amount of a compoundselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 82. The method of claim81, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 83. The method of claim81, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 84. The method of claim81, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 85. The method of claim81, wherein the tumor cell is from a human subject.
 86. The method ofclaim 81, wherein the tumor cell is a chronic myelomonocytic leukemia,acute myeloid leukemia, breast cancer, non-small cell lung cancer(NSCLC), colorectal cancer (CRC), esophageal cancer, gastric cancer,squamous-cell carcinoma of the head and neck (SCCHN), or ovarian cancercell.